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Corresponding author. Department of Gastroenterology and Hepatology, The Chinese PLA General Hospital, Beijing 100853, China. Tel.: +86 15901139776; fax: +86 68180325.
The purpose of the study was to investigate the role of iodine-125 seed implantation, guided by endoscopic ultrasound (EUS) and/or percutanous ultrasound, in patients with unresectable pancreatic carcinoma after relief of obstructive jaundice using endoscopic retrograde cholangiopancreatography (ERCP).
Methods and Materials
A total of 101 patients with obstructive jaundice due to unresectable pancreatic carcinoma were enrolled between January 2010 and December 2017 in this retrospective study. Of these patients, 50 underwent implantation of iodine-125 seeds under EUS and/or percutaneous ultrasound guidance after receiving a stent via ERCP (treatment group), and 51 received a stent via ERCP without undergoing seed implantation (control group). The clinical data and therapeutic outcomes of these patients were analyzed.
Results
Compared with the control group, the treatment group obtained significant relief of abdominal pain at the 1-week, 1-month, and 3-month followup (p < 0.05), with a significantly lower visual analog scale pain score (p < 0.05). The treatment group obtained a longer median survival (8.8 vs. 6.5 months, p = 0.02), longer median duration of stent patency (10.8 ± 1.4 vs. 6.9 ± 0.8 months, p = 0.02), and prolonged average time to gastric outlet obstruction (6.8 ± 1.6 vs. 5.3 ± 1.3 months, p = 0.02). Differences between liver function and appetite for the two groups were not significant (p > 0.05 and p = 0.59, respectively).
Conclusions
Iodine-125 seed implantation after relief of obstructive jaundice via ERCP prolongs survival, biliary stent patency, and time to gastric outlet obstruction and improves patient quality of life by relieving pancreatic pain in patients with unresectable pancreatic carcinoma.
). Most patients are diagnosed with end-stage disease after finally developing typical signs and/or symptoms such as obstructive jaundice or acute cancer pain. The 5-year overall survival (OS) for patients with locally advanced pancreatic cancer is about 4%; the median OS time ranges from 9 to 15 months and can be 3 to 6 months shorter in patients with metastatic disease (
). Less than 20% of patients with locally advanced disease are eligible for surgery; those who do undergo surgery are at risk for severe surgical complications and show a high recurrence rate (
). Therefore, management of biliary obstruction is important for patients with advanced pancreatic carcinoma, and decompression of biliary obstruction by the insertion of a stent has been accepted as a palliative procedure for patients with unresectable pancreatic carcinoma or who are unwilling to undergo surgery. Unfortunately, stenting has a limited effect on survival time (
) and stent patency. Iodine-125 seeds, which can deliver a high radiation dose to the target tissue with reduced damage to the surrounding tissues, have been reported to be a feasible treatment for malignant biliary obstruction in animal and human studies (
Malignant obstructive jaundice treated with intraluminal placement of Iodine-125 seed strands and metal stents: An analysis of long-term outcomes and prognostic features.
). However, the effects of seed implantation in patients with unresectable pancreatic carcinoma who have obtained relief of obstructive jaundice by stent placement via endoscopic retrograde cholangiopancreatography (ERCP) need further exploration.
Therefore, in this study, we aimed to investigate the effects of iodine-125 seed implantation performed under endoscopic ultrasound (EUS) and/or percutaneous ultrasound guidance in patients with unresectable pancreatic carcinoma after relief of obstructive jaundice by stent placement via ERCP.
Methods and materials
Patients
Between January 2010 and December 2017, a total of 101 patients were selected for this retrospective study. All patients had unresectable pancreatic cancer with obstructive jaundice and requested endoscopic palliative treatment. The study inclusion criteria were as follows: pancreatic carcinoma confirmed by examination of a fine-needle aspiration biopsy specimen and CT imaging or previous surgical procedures, jaundice associated with carcinoma-related biliary obstruction, ineligible for curative surgery for a primary pancreatic tumor, and unwilling to receive external beam radiotherapy (EBRT) and chemotherapy. The exclusion criteria were as follows: cardiovascular complications, and pulmonary or kidney dysfunction. Ethical approval was obtained from the Regional Ethics Committee of our hospital, and written informed consent was obtained from all patients.
Methods
We selectively cannulated the bile duct with a guidewire under therapeutic duodenoscopy (TJF-240/TJF-260V; Olympus, Tokyo, Japan). All patients underwent ERCP, which was used to identify stenosis of the biliary and pancreatic ducts. Either a plastic stent (Cook Medical, Bloomington, IN) or a fully covered self-expandable metal stent (Boston Scientific, Marlborough, MA) were implanted, with the distal end of the stent placed at least 2 cm past the area of obstruction stenosis under the guidance of a guide wire. After biliary obstruction was relieved, each study patient chose the subsequent treatment option after receiving an explanation of the advantages and disadvantages of chemotherapy, EBRT, and iodine-125 seed implantation.
The radioactive iodine-125 seed (China Isotope & Radiation Co., Ltd., Beijing, China) consists of a titanium capsule containing iodine-125 adsorbed onto an inactive palladium rod. The half-life of iodine-125 is 59.4 days; it decays by electron capture with subsequent emission of characteristic photons and electrons. The electrons are absorbed by the titanium wall of the iodine-125 seed. The principal photon emissions consist of 27.4- and 23.9-keV fluorescent x-rays from the inactive palladium rod. The half-value thickness of lead for iodine-125 is 0.025 mm and of tissue is 20.0 mm. Thus, a 0.25-mm lead sheet will provide >99.0% reduction in exposure. Before the procedure, tumor volume was measured in all patients by abdominal CT, and the value was used to calculate the number of radioactive iodine-125 seeds required for each patient in the treatment group.
Patients undergoing implantation of seeds under EUS and/or percutaneous ultrasound guidance after receiving stent implantation via ERCP were regarded as the treatment group, whereas patients who received stenting without seed implantation were regarded as the control group. Patients in the treatment group received intravenous or local anesthesia for iodine-125 seed implantation under EUS (Olympus Corporation, Tokyo, Japan) and/or percutaneous ultrasound guidance. EUS was used to measure the volume, morphology, and margins of the tumor, along with its relationship with surrounding tissues. Iodine-125 seeds with an apparent activity of 0.6 mCi/seed were used. The seeds were sterilized at a high temperature and installed in radiation-resistant metal clips before placement into a MICK 200-TPV applicator that was later connected to a needle used in the procedure. While avoiding the blood vessels and the pancreatic duct, a 19-gauge fine-needle aspiration needle was inserted into the distal edge of the mass under ultrasound guidance, the stylet was removed, and the seeds were inserted into the lumen of the needle. The seeds were then implanted in the tumor at 1- to 2-mm intervals, while the needle was drawn backward. This study uses a simple dose calculation method based on our clinical experience. With a general density of 5–10 seeds/cm, the seeds were aligned in a straight line within the tumor. The distances between needle puncture sites were such that the ultrasound images did not overlap; that is, the location of the second needle puncture was based on the inability to see the seeds implanted by the first needle. The rule of treatment is to allow the seed to fill the entire tumor as much as possible during implantation. Postoperative adjuvant therapy was generally recommended for all patients, including EBRT, chemotherapy, and molecular-targeted therapy. In addition, radiation could not be detected at a distance of 3 feet, and a minimal amount of radiation could be detected within a distance of 3 feet.
Postoperative followup
After treatment, patients were intensively observed for at least 6 h and remained fasting for at least 12 h, which was also true for patients undergoing conventional ERCP. If medically significant events did not occur, the patient was discharged from the hospital and was monitored at 1 week, 1 month, and then at 3-month intervals by routine blood studies, liver function assessment (alanine aminotransaminase and total bilirubin levels), and abdominal CT or ultrasound. The patient's overall condition, pain score, and appetite were assessed and recorded during followup visits. The visual analog scale (VAS) pain score was used to assess abdominal pain, and WHO criteria were used to assess tumor response. If the area where the seed planted is shrinking, and the tumor is growing at locations where the seeds were not implanted, additional iodine-125 seeds were placed.
Statistical analysis
The differences between numerical variables in the two groups were analyzed by the independent samples t-test, whereas the intrablock analysis of differences in each group before and after treatment used the paired-samples t-test. The chi-squared test was used to analyze differences between ranked variables. The Kaplan-Meier method was used for survival analysis, duration of biliary stent patency, and time to gastric outlet obstruction. All statistical analyses were performed by SPSS software, version 19.0. Statistically significant differences were indicated by a p-value < 0.05.
Results
Patient characteristics are summarized in Table 1. Fifty-one patients treated with endoscopic biliary drainage alone were regarded as the control group, and 50 patients choose treatment that combined what the control patients received with implantation of iodine-125 seeds. Differences between age, gender, tumor stage and location, symptoms, performance status, and pathology of the 2 groups were not significant.
Biliary stents were placed in all 101 patients, with 6/51 (11.8%) and 8/50 (16%) patients also receiving a pancreatic duct stent among the control and treatment groups, respectively. Iodine-125 seeds were successfully implanted in 100% of the patients undergoing seed implantation; implantation was performed under guidance by percutaneous ultrasound or EUS in 22 (44%) and 28 (56%) patients, respectively. The mean number of seeds implanted was 31.8 (range, 13–50), which included 5 patients who underwent a second seed implantation procedure during followup.
A total of 17 patients developed postoperative complications in the treatment group; postoperative complications were higher than those of patients in the control group (34% vs. 9.8%; p = 0.003). The most common complication was transient abdominal pain, which mainly appeared 1–2 days after implantation of the seeds and was related to inflammation resulting from the procedure. Transient abdominal pain occurred in 7/50 (14%) patients in the treatment group. A total of 6/50 (12%) patients in the treatment group developed short-term signs and symptoms which might have been associated with γ-rays emitted by the radioactive iodine-125 seeds, which included vomiting in 2 patients and abdominal distension and loss of appetite in 4 patients. All of these problems were alleviated by gastrointestinal motility agents and mucosal protective agents, followed by pancreatitis in the two groups and 1 patient developing cholangitis in the control group. All these patients recovered with conservative management. Seed migration into the tail of the pancreatic duct occurred in 1 patient, but migration-related complications did not occur. Other serious complications such as bleeding, perforation, and radiation duodenitis were not observed during the followup period (Table 2).
Table 2Endoscopic intervention and procedure-related complications
Both the treatment and control groups showed improved liver function after treatment, and the differences between the liver function test results of the two groups were not significant (p > 0.05) (Table 3). Albumin levels in both groups decreased slightly at 7 days after treatment. A total of 84 patients from both groups complained of abdominal and back pain before treatment intervention. The VAS pain score of the control group did not significantly decrease during the followup period, decreasing from 6.6 ± 1.8 to 5.9 ± 1.9 at 1 week after treatment intervention (p > 0.05). By contrast, the VAS pain score of the treatment group patients decreased significantly from 6.6 ± 2.0 to 3.2 ± 1.7 at 1 week after seed implantation (p < 0.05). Although the score slightly increased to 3.7 ± 1.6 at the 1-month followup and to 4.0 ± 1.9 at the 3-month followup, the VAS pain scores remained significantly lower than the preoperative VAS score (p < 0.05). The differences between abdominal pain of the two groups in improvement were significant at 1-week, 1-month, and 3-month followups (p < 0.05). At the 6-month followup, the difference between the VAS pain scores of the two groups was not significant (Table 4). More than half the patients in both groups showed improved appetite 1 month after treatment, whereas about one-third reported either no change or worsening anorexia. The difference between the two groups was not significant (p = 0.59). The difference between the rates of gastric outlet obstruction recurrence in the two groups was not significant (16.0% vs. 25.5% in the treatment and control groups, respectively); however, the mean duration of time to recurrence of gastric outlet obstruction was longer for the patients undergoing seed implantation than for the control patients (6.8 ± 1.6 months vs. 5.3 ± 1.3 months, p = 0.02).
Table 3Changes in laboratory values after stenting
Variable
Control group
Treatment group
p-value
ALT (d0, u/L)
136.3 ± 12.3
113.7 ± 17.6
0.64
ALT (d7, u/L)
76.7 ± 10.1
47.5 ± 8.4
0.33
ALT (d7-d0, u/L)
−59.5 ± 11.7
−66.3 ± 10.5
0.84
TBIL (d0, umol/L)
124.6 ± 11.9
106.7 ± 10.5
0.66
TBIL (d7, umol/L)
61.4 ± 8.4
47.1 ± 7.9
0.22
TBIL (d7-d0, umol/L)
−63.2 ± 10.2
−59.5 ± 9.2
0.74
Alb (d0, g/L)
36.7 ± 4.9
37.0 ± 4.1
0.63
Alb (d7, g/L)
34.2 ± 3.4
35.1 ± 6.4
0.22
Alb (d7-d0, g/L)
−2.5 ± 3.8
−1.9 ± 3.8
0.50
ALT = alanine transaminase; TBIL = total bilirubin; Alb = albumin.
The median duration of followup was 12 months (range, 2.4–30 months). The duration of biliary stent patency was 10.8 ± 1.4 months in the treatment group vs. 6.9 ± 0.8 months in the control group, which was significant (p = 0.02). The rates of overall positive response between the treatment group vs. the control group were 38.0% and 0%, respectively. The rate of progressive disease occurring in the treatment group was lower than that in the control group (16% vs. 58.8%, respectively) at the 1-month follow-up. The median OS time of the control group was 6.50 months (range, 0.9–17.1 months). The median OS time of the treatment group was 8.80 months (range, 2.2–21 months), as shown by the Kaplan–Meier cumulative curves (Fig. 1). The difference between the OS times of the control and the treatment groups was significant (p = 0.02). The 6- and 12-month survival rates were 69.0% and 27.2%, respectively, in the treatment group and 53.8% and 11.2%, respectively, in the control group. Of the 101 patients in both groups, 92 died of cancer-related cachexia or liver failure and 9 patients survived to the end of followup. Of the patients in the treatment group, 13 patients lived longer than 12 months.
Fig. 1Kaplan-Meier curve showing overall survival curves of the group of patients undergoing endoscopic stent placement and iodine-125 seed implantation and of the group of patients undergoing endoscopic stent placement only.
The effective treatment of patients with unresectable pancreatic cancer remains challenging because most are diagnosed only when they present with obvious symptoms. Less than 20% of patients with late-stage pancreatic cancer are eligible for surgery (
). Obstructive jaundice is a common manifestation of pancreatic cancer and has been reported to occur in up to 70% of patients with cancer of the head of the pancreas (
). Although performing preoperative biliary drainage routinely is a contentious issue because of its limited beneficial effect on the postoperative outcome and the increased morbidity related to biliary drainage (
Preoperative biliary stenting versus operation first in jaundiced patients due to malignant lesions in the pancreatic head: A meta-analysis of current literature.
), the placement of an endoscopic stent as part of the palliative management of patients with unresectable pancreatic carcinoma is extremely effective at providing symptomatic relief and improving patient quality of life (
), and stent patency is of limited duration. External radiotherapy is recommended for patients with advanced pancreatic carcinoma and might decrease tumor burden and improve signs and symptoms (
Phase III trial comparing intensive induction chemoradiotherapy (60 Gy, infusional 5-FU and intermittent cisplatin) followed by maintenance gemcitabine with gemcitabine alone for locally advanced unresectable pancreatic cancer. Definitive results of the 2000-01 FFCD/SFRO study.
), and external radiotherapy also requires daily visits to the hospital, which is not conducive to a good quality of life. Importantly, stereotactic radiotherapy provides interstitial irradiation to destroy cancer cells and has been proven to be a suitable option for patients ineligible for surgery (
Unresectable locally advanced pancreatic cancer: A multimodal treatment using neoadjuvant chemoradiotherapy (gemcitabine plus stereotactic radiosurgery) and subsequent surgical exploration.
). Iodine-125 seeds can deliver a large radiation dose to the target tissue with less damage to the surrounding tissues and have been reported to be a feasible treatment for patients with malignant biliary obstruction (
Malignant obstructive jaundice treated with intraluminal placement of Iodine-125 seed strands and metal stents: An analysis of long-term outcomes and prognostic features.
Malignant obstructive jaundice treated with intraluminal placement of Iodine-125 seed strands and metal stents: An analysis of long-term outcomes and prognostic features.
) was reported to be feasible treatment that provides survival benefit and prolonged stent patency in patients with malignant obstructions. However, few studies have compared the efficacy of stent placement combined with implanted iodine-125 seeds with conventional stent placement alone in patients with unresectable pancreatic carcinoma and obstructive jaundice.
In this study, we implanted seeds in patients with unresectable pancreatic cancer under EUS and/or percutaneous ultrasound guidance. We found that the median survival of the treatment group was 8.8 months, which was 2.3 months longer than the survival of the control patients, who underwent stenting alone. A meta-analysis has found that iodine-125 seed implantation brachytherapy alone was associated with a survival of 8.98 months (
) in patients with advanced pancreatic cancer, which is consistent with our result. However, the presence of jaundice in patients with pancreatic cancer is predictive of worse survival. Our study results, however, are important for patients with advanced pancreatic cancer present with jaundice.
Invasion or compression of the distal stomach or proximal duodenum by pancreatic cancer is a common cause of gastric outlet obstruction, with an estimated 15–20% of patients developing gastric outlet obstruction (
). We found that patients undergoing seed implantation showed a prolonged mean time to gastric outlet obstruction, which, to the best of our knowledge, has not yet been reported by other study investigators. Our result might have been because implanted iodine-25 seeds inhibited the growth and invasion of tumors. None of patients died perioperatively or developed fatal complications. The rate of acceptable complications was also low. After seed implantation, the patients' clinical parameters showed significant improvement. Abdominal pain, especially, was controlled, which is key for improving the quality of life in patients with pancreatic cancer. However, the VAS pain score increased to the preoperative level at the 6-month followup, which can be accounted for by decay of the iodine-125 seeds. The control group showed improved appetite for a short time, but the group's cancer pain was not adequately relieved. The difference between the results of the two study groups might be accounted for by the inhibition of tumor growth in response to the radiation emitted by the iodine-125 seeds. Interestingly, appetite improvement did not differ between the two groups, which suggests that seed implantation has no significant effect on improving appetite. The relief of obstructive jaundice provided by endoscopic retrograde biliary drainage might play an important role in protecting the balance and barrier function of the gastrointestinal tract. There was no statistically significant difference in improvement in liver function between the groups. Based on previous reports, we believe that both groups experienced biliary drainage that relieved obstructive jaundice and related complications such as intestinal flora imbalances and bacteremia (
[Endoscopic ultrasonography (EUS)-guided transluminal cholangiodrainage (EUCD) - a novel option of interventional endoscopy in the interdiciplinary management of obstructive jaundice].
). Albumin levels decreased slightly 7 days after treatment in both groups. This might be attributable to the perioperative fasting undertaken by both groups and the levels improved in subsequent followup.
Previous studies have reported that iodine-125 seed implantation can inhibit tumor growth in patients with pancreatic cancer more directly and effectively than external radiotherapy, with less damage to normal surrounding tissue (
). Basic research focused on the mechanism by which radioactive iodine-125 seeds are beneficial in patients with pancreatic carcinoma indicates that irradiation might inhibit pancreatic cancer tumor growth by changing DNA methyltransferase expression patterns and inducing programmed cell death of the PANC-1 cell line (
). Our study observed changes in tumor growth in the treatment group compared with the control group, and the overall rate for positive response after seed implantation was obviously higher, with fewer patients developing progressive disease. Thus, we are fully convinced that radioactive iodine-125 seeds combined with endoscopic drainage plays a direct role in restricting tumor growth in patients with pancreatic cancer, which to some extent explains the resulting longer survival time, longer median duration of stent patency, and longer mean time to gastric outlet obstruction in patients who received implanted seeds, compared with the control group, amelioration abdominal pain, and appetite. Furthermore, seed implantation has an additional merit in that daily visits to the hospital are not needed, as opposed to treatment with EBRT, which improves patient quality of life.
Implantation of iodine-125 seeds combined with endoscopic drainage shows particular advantage for treating patients with advanced pancreatic cancer, with longer survival times than traditional palliative treatment. It represents an additional option for patients with late-stage pancreatic cancer because of its effect on inhibiting tumor growth, alleviating cancer pain, and prolonging survival time, which greatly benefits patient quality of life, with few risks (seed migration) and acceptable complications, such as pancreatitis, transient pain, vomiting, and abdominal discomfort, which can be controlled by conservative treatment.
The shortcomings of seed implantation are that neither percutaneous ultrasound nor endoscopic ultrasound guidance can guarantee uniform distribution of seeds in the tumor. Another disadvantage of iodine-125 seed implantation is the impediment to close personal contact between family members, such as hugging and sexual activity. After seed implantation, the patient should remain at farther than 1 m from others to protect them from radiation. Furthermore, further multicenter and randomized clinical studies are needed to verify the results of our study because the relatively small sample size and short followup period of our study might reduce its predictive power.
Conclusion
The implantation of radioactive iodine-125 seeds combined with stenting provides a median survival of 8.8 months in patients with advanced pancreatic cancer, which is 2.3 months longer than the survival of control patients. It is a feasible, safe treatment that effectively improves cancer pain, restricts tumor growth, and prolongs biliary stent patency and the time to gastric outlet obstruction, all of which markedly improves the quality of life of patients with late-stage pancreatic cancer.
Acknowledgments
The authors gratefully thank the Project of Capital Characteristic Clinical Medicine Application Development Fund of Beijing Municipal Science and Technology Commission (D101100050010043) support for this study.
Malignant obstructive jaundice treated with intraluminal placement of Iodine-125 seed strands and metal stents: An analysis of long-term outcomes and prognostic features.
Preoperative biliary stenting versus operation first in jaundiced patients due to malignant lesions in the pancreatic head: A meta-analysis of current literature.
Phase III trial comparing intensive induction chemoradiotherapy (60 Gy, infusional 5-FU and intermittent cisplatin) followed by maintenance gemcitabine with gemcitabine alone for locally advanced unresectable pancreatic cancer. Definitive results of the 2000-01 FFCD/SFRO study.
Unresectable locally advanced pancreatic cancer: A multimodal treatment using neoadjuvant chemoradiotherapy (gemcitabine plus stereotactic radiosurgery) and subsequent surgical exploration.
[Endoscopic ultrasonography (EUS)-guided transluminal cholangiodrainage (EUCD) - a novel option of interventional endoscopy in the interdiciplinary management of obstructive jaundice].
Financial disclosure: The authors report that they do not have any proprietary or commercial interest in any product mentioned or concept discussed in this article.
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