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A novel combination of percutaneous stenting with iodine-125 seed implantation and chemotherapy for the treatment of pancreatic head cancer with obstructive jaundice
Insertion of radioactive strips through the biliary stent has been reported to offer longer survival and patency than an uncovered conventional self-expanding metal stent in patients with unresectable malignant biliary obstruction. The aim of this study was to investigate the safety and effectiveness of intraluminal brachytherapy combined with 125I seed implantation and transarterial infusion chemotherapy for the treatment of pancreatic head cancer with obstructive jaundice.
Method
From October 2012 to January 2018, 21 consecutive patients diagnosed with biliary obstruction caused by locally advanced, nonmetastatic pancreatic cancer with cytologically or histologically confirmed by biopsy were enrolled and receive treatment with intraluminal brachytherapy using 125I seed strand and CT-guided percutaneous radioactive seed implantation therapy. The procedure-related and radiation complications were assessed. The outcomes were measured in terms of stent patency, patient survival, complications related to the procedure.
Result
One of the 22 patients (4.5%, 1/22) with pancreatic head cancer failed to perform the above procedure because the guidewire was unable to pass through the obstruction segment. The remaining 21 patients (95.5%, 21/22) with pancreatic head cancer with obstructive jaundice were successfully placed with biliary stents and radioactive strips through drainage tubes. The median number of 125I seeds loaded was 15, ranging from 12 to 17. After the chemotherapy with gemcitabine and cisplatin, no adverse reaction of Grade Ⅲ ∼ Ⅳ occurred in all cases. Median stent patency was 12.50 months (95% CI: 10.26, 14.74). By May 2019, all 21 patients had died, with overall survival of 5.2–23.3 months, with a median survival of 13.20 months (95% CI: 10.96, 15.44).
Conclusion
Percutaneous 125I seed implantation combined with insertion of radioactive strips through the biliary stent has the characteristics of less trauma, fewer complications, simple operation, and so on. These procedures bring remission of obstructive jaundice combined with the increased survival for the treatment of obstructive jaundice caused by unresectable pancreatic head cancer if follow-up chemotherapy is carried out. The long-term efficacy of this treatment combination needs to be confirmed by further multicenter, large sample size prospective randomized controlled studies.
) are not eligible for a potentially curative surgical resection due to distant metastasis or local invasion. When it is located in the head of the organ (65% of cases) (
), which is followed by further active chemotherapy. Over the past 30 years, stenting the biliary obstruction has become widely accepted as the preferred palliation modality for patients with unresectable malignant biliary obstruction to relieve pain, pruritus, cholangitis, and jaundice (
). Endoscopic stent placement may result in drainage of the entire biliary tree without the need for an external device in patients with a distal biliary obstruction (
Pathologic stage of prostatic ductal adenocarcinoma at radical prostatectomy: effect of percentage of the ductal component and associated grade of acinar adenocarcinoma.
), while patients with proximal biliary tract obstruction may need a percutaneous puncture approach to the targeted bile ducts. Although various stents have been designed to improve clinical efficacy, there are no significant differences in survival or quality of life (
). The implanted stents with no therapeutic effect have been occluded over time for various reasons, such as tumor ingrowth or overgrowth, food impaction, mucosal hyperplasia, and biliary sludge (
) by directly damaging the DNA double helix structure. Recently, self-expandable stents using 125I seed strand was demonstrated to offer a significant improvement in median survival in patients with unresectable malignant biliary obstruction (
) compared with patients who received stent placement alone. Whether this approach is safe and effective for patients with unresectable pancreatic head cancer needs further study. Therefore, this study was performed to evaluate the benefit of intraluminal brachytherapy for the treatment of locally advanced pancreatic head cancer with biliary obstruction.
2. Method
2.1 Patients
A single-center, retrospective single-arm pilot study, began from October 2012 and ended in January 2018, was approved by the ethics committee review board of Fujian Medical University Union Hospital, and written informed consent was obtained from all patients prior to the procedure. Patients were eligible if they had a biliary obstruction caused by locally advanced, nonmetastatic pancreatic cancer with cytologically or histologically confirmation by biopsy; unresectable pancreatic head cancer; age range 18–80 years old, adequate hematologic, cardiac, renal and liver function, and Eastern Cooperative Oncology Group (ECOG) performance status 0–2. Exclusion criteria were as follows: ECOG performance status >2; other types of pancreatic carcinoma, and pancreatic carcinoma with distant metastases; percutaneous transhepatic cholangiography procedure was contraindicated (platelet count below 50 × 109/L or coagulation disorder), liver or renal failure; cardiac dysfunction; or end-stage disease and patients who were uncooperative during the procedure or not capable of providing authorization and signature. Finally, 22 patients (9 female, 13 male; age range, 39–80 years; median age, 62 years) receiving stent treatment were included in this retrospective single-arm study (Table 1).
Disease stage was assessed based on histology after forceps or needle biopsy, computed tomography (CT), and/or magnetic resonance imaging findings (mass in the head of the pancreas with delayed enhancement), plus laboratory and clinical findings. The primary endpoint was stent patency, calculated as the interval between stent placement and the first episode of stent restenosis. The stent restenosis was defined as the reappearance of biliary stenosis and symptoms of jaundice with elevated bilirubin levels. The secondary endpoints included technical success, complications, relief of jaundice, and overall survival. Relief of jaundice was defined as the reduction of biliary obstruction related symptoms such as pruritus, jaundice, and total bilirubin after treatment with sent implantation. The overall survival was defined as the time from stent implantation to death or the last follow-up. Complications were accessed according to the Common Terminology Criteria for Adverse Events (CTCAE 4.02).
2.3 Procedures
To minimize the delivery sheath, we performed the catheter loading 125I seed stripes combined with biliary stent implantation (Nanjing Micro Invasive Medical Inc., Nanjing, China). 125I seeds were contained in polytetrafluoroethylene tubes to make a 125I seed strand. The diameter and length of the stents were based on the measurement of the lesions according to magnetic resonance cholangiopancreatography, cholangiography, and/or enhanced CT findings. The 125I seeds have a radioactive half-life of 59.6 days and dual principal photon emissions, X-ray energy of 27.4–31.4 keV, and 35.5 keV γ-ray (
). The number, dosage, location, and distribution of 125I seeds were calculated based on the size and extent of the individual tumors. The quantified radiation dose was set at 130 Gy that was assessed again by postimplantation dosimetry.
A percutaneous intrahepatic biliary tract puncture was performed under fluoroscopic and ultrasonic guidance. Before stent placement, the length and extent of the tumor were determined by three-dimension computed tomography (CT) enhanced scan or magnetic resonance cholangiopancreatography. Then, a standard percutaneous transhepatic biliary drainage (PTBD) procedure was scheduled 2 weeks before and removed during bare-metal stent implantation (Fig. 1a). Following the dilatation of the occluding bile duct with a balloon dilator catheter, the self-expanding metal stent assembled into a 7-F sheath was introduced into the bile duct over a stiff guidewire to cover the lesion area (Figs. 1b and 1c). According to the length of biliary stricture or obstruction, the different number of radioactive particles were selected to prepare radioactive particle strips, and the particle strips were fixed on the catheter with 5–0 silk thread. The catheter containing the particle strip was sent into the area to be irradiated through the 8F biliary drainage tube under fluoroscopy (Fig. 1d).
Fig. 1(a) Pancreatic head carcinoma with obstructive jaundice underwent PTBD, indicating obstruction of the lower biliary tract. (b) Biliary balloon dilation. (c) Biliary metal stenting. (d) Radioactive particle strip. (e) CT-guided percutaneous pancreatic head cancer radioactive particle implantation. (f, g) Digital subtraction angiography descending pancreaticoduodenal arterial chemotherapy infusion.
After the jaundice relief and the liver function recovery, CT-guided percutaneous 125I seed implantation was performed to treat pancreatic head cancer. CT or MR enhancement of the pancreas was performed first to observe the relationship between the tumor and peripheral blood vessels and viscera. Subsequently, appropriate implantation plans were made, including determining the location and direction of the guide needle in the target area. The seed spacing was 10 mm, and 5–37 seeds were implanted in each patient. The patient fasted and rested in bed for 24 h after the operation, and was routinely given drugs such as hemostatic agents, antacids, and somatostatin to avoid bleeding, pancreatic fistula, and other complications.
Seldinger puncture technique was employed to puncture the right femoral artery, and a 4Fr or 5Fr vessel sheath was placed. A 4Fr or 5Fr RH or Cobra catheter was inserted into the celiac artery and superior mesenteric arteriography, respectively, to observe the blood supply of the tumor. The catheter was inserted in the gastroduodenal artery for chemotherapy infusion. Chemotherapy with gemcitabine and cisplatin was recommended, and the doses used were 1/2 of the systemic doses (gemcitabine 500 mg/m2, cisplatin 35 mg/m2, once in 3 weeks). The complete flow diagram of procedures is shown in Fig. 2.
One day postoperatively, a CT scan was scheduled to reveal the location and radioactivity of 125I seeds. Routine follow-up examinations were performed monthly for 6 months, and then every 2 months after stent placement. Follow-up parameters consisted of blood laboratory examinations (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and gamma-glutamyl transpeptidase), clinical findings (signs and symptoms related to the biliary obstruction), and outpatient imaging (US or CT) results. The survival benefit was assessed using time till death. Follow up was performed by regular outpatient clinic visits, telephone for the results of imaging examinations, and laboratory investigations from our hospital.
2.5 Data analysis
Continuous variables were expressed as mean ± SD. Laboratory test changes were evaluated using paired-samples t-test. A p value < 0.05 considered statistically significant. The Kaplan-Meier technique was employed to estimate the stent patency and overall survival. Statistical analysis was performed with statistical software (SPSS, version 22.0, IBM).
3. Results
3.1 Technique success
There were no deaths during the perioperative period. One of the 22 patients (4.5%, 1/22) with pancreatic head cancer failed to perform the above procedure because the guidewire failed to pass through the obstruction segment. Thus, only percutaneous transhepatic cholangiography and drainage (PTCD) and percutaneous radioactive seed were implanted for this patient. The remaining 21 patients (95.5%, 21/22) with pancreatic head cancer with obstructive jaundice were successfully placed with biliary stents and radioactive strips through drainage tubes. Stents with diameters of 8 mm and lengths of 6–8 cm were chosen. The median number of 125I seeds loaded was 15, ranging from 12 to 17. Total bilirubin and conjugated bilirubin significantly decreased from 202.10 ± 76.62 mmol/L to 87.44 ± 58.37 mmol/L, (p < 0.01) and from 60.22 ± 15.53 mmol/L to 36.24 ± 10.47 mmol/L, (p < 0.01) 1 week after successful bile drainage. After the recovery of liver function, percutaneous radioactive seed implantation was successfully carried out, among which 4 cases had bleeding observed by CT during the operation, and were improved after treatment with compression hemostasis and hemostatic drugs. During the operation period, no serious complications such as massive hemorrhage, pancreatitis, pancreatic fistula, perforation of the digestive tract, and abdominal abscess were found. One month after the procedure, the mean total bilirubin of serum decreased to (36.07 ± 13.32) mmol/L, and the direct bilirubin decreased to (28.36 ± 7.61) mmol/L, and bilirubin of all patients decreased to normal or nearly normal, with statistically significant difference (p < 0.01). Abdominal pain and lower back pain were relieved or disappeared to varying degrees from 1 week after surgery. The 21 patients received chemotherapy with gemcitabine and cisplatin 57 times, averaging 1.8 times per person.
3.2 Complication
Abdominal effusion occurred in two patients (9.6%, 2/21) with varying amounts, and the pancreatic fistula was excluded from the examination. Adequate nutritional support and somatostatin treatment were given, and the abdominal effusion disappeared 1 to 4 weeks after the operation. Three patients (14.29%, 3/21) presented abdominal distension, nausea, vomiting, loss of appetite, and other gastrointestinal symptoms, and two patients (9.6%, 2/21) presented fever, which was relieved after antiinfection and symptomatic treatment. As shown by radiography and CT scan, two particles migrated to the liver in one patient (4.8%, 1/21) after surgery, and no adverse reactions were found in the patient during follow-up. After the chemotherapy with gemcitabine and cisplatin, no adverse reaction of Grade Ⅲ ∼ Ⅳ occurred in all cases, while adverse effects of Grade Ⅰ∼Ⅱ were frequently observed: Six patients had lower white blood cell count of Grade Ⅰ∼Ⅱ; Two patients had a lower blood platelet count of Grade Ⅰ∼Ⅱ; Three patients had symptoms of vomiting of Grade Ⅰ∼Ⅱ; Six patients had elevated total bilirubin of Grade Ⅰ∼Ⅱ; Seven patients had elevated alanine transaminase of Grade Ⅰ∼Ⅱ (Table 2).
All patients were able to evaluate the clinical benefit response. Among them, the analgesic dosage of 13 patients decreased by more than 50%, and the Visual Analog Scale/Score of pain intensity decreased by more than 50% after treatment (Table 3); Physical condition of eight patients improved obviously; Body mass increased by ≥ 7% in five patients for more than 4 weeks. A total of 15 patients met the criteria for clinical benefit, with a total clinical benefit rate of 71.4%.
Median stent patency was 12.50 months (95% CI: 10.26, 14.74). In one case, the distal hilar obstruction of the stent occurred due to intrahepatic metastasis, and percutaneous transhepatic biliary drainage was undergone to relieve jaundice; No obstructive jaundice due to stent obstruction was found during the remaining observation period. By May 2019, all 21 patients had died, with overall survival of 5.2–23.3 months, with a median survival of 13.20 months (95% CI: 10.96, 15.44).
4. Discussion
According to the epidemiological survey data, the incidence of pancreatic cancer increased yearly (
). Pancreatic head cancer is often accompanied by obstructive jaundice. And if jaundice is not improved in time, liver function, kidney function, coagulation mechanism will rapidly deteriorate, endangering the life of the patient (
). In most cases, patients with newly diagnosed pancreatic cancer are eligible for a potentially curative surgical resection due to distant metastasis or local invasion. Although the surgical resection rate of malignant obstructive jaundice has been greatly improved, it is still only about 20% (
Percutaneous transhepatic biliary drainage and self-expanding metal stent implantation have become the preferred treatment for malignant biliary obstruction due to their advantages of minimally invasive and repeatability (
). It is also a better choice for pancreatic head cancer with obstructive jaundice and is even used as an effective decompression method before operation (
). A large number of clinical applications have demonstrated that the long-term efficacy of metal biliary stent was significantly better than plastic stent or external nasobiliary drainage (
). The failure of tumor control was an important reason for the unimproved survival rate. In order to prevent occlusion from tumor ingrowth, the method of radiation therapy by inserting a radioactive source into the lumen came into being (
). Because of the large size of pancreatic head carcinomas and characteristic of eccentric nonenveloping bile duct growth, the effective irradiation range of 20 mm for radioactive particles placed through the biliary tract is not sufficient (
). To further control the residual lesions, the irradiative exposure of 125I seeds, percutaneous radioactive particle implantation should be combined with the radioactive particle strips in the biliary tract to form a complementary irradiation effect, effectively reducing the blind area of radiotherapy, so as to achieve the goal of controlling the pancreatic head tumor to the maximum extent. Simple metal stent implantation and percutaneous radioactive seed implantation could neither effectively inhibit the growth of peripheral tumors leading to biliary stenosis nor maintain the long-term patency of the stent.
A previous study reported that the catheter loading 125I seed stripes combined with biliary stent implantation had a good clinical effect on relieving malignant biliary tract obstruction (
). For pancreatic head cancer with biliary obstruction belonging to malignant biliary lesions, this combination was used in this study, and a good effect was also achieved. The fact that 125I seeds had favorable biological effects on pancreatic cancer has been proved in some studies (
). The seeds were evenly distributed in the stent, forming a cylindrical dose distribution to protect the stent, thereby preventing occlusion from tumor ingrowth. In the treatment of esophageal cancer, the advantages of radioactive seeds in prolonging the patency of the stent were also found (
). Predictive factors for survival outcomes after relieving obstructive jaundice include tumor features, ECOG, and age. In addition to the above factors, stent patency was an independent risk factor for survival, with a correlation coefficient as high as 0.644 (
For pancreatic cancer patients, external radiotherapy (gamma knife, etc.) can only affect the cells in a part of the tumor cell reproduction cycle, while the tumor cells in other phases can still recover quickly (
). It is also difficult to reduce the damage to the normal tissues surrounding the pancreas, which limits its clinical application. The radiation produced by the implantation of 125I seeds in the tumor tissue is not strong, but it can continuously act on the pancreatic tumor cells (
). It has been demonstrated that 125I brachytherapy increased the apoptotic rate and changed the expression patterns of DNA methyltransferases in pancreatic cancer cells, leading to programmed cell death (
). Therefore, after a sufficient radioactive half-life, tumor cells are constantly damaged, which can make all tumor cells lose the ability to reproduce, thus achieving a complete therapeutic effect. Compared with tumor cells in different division cycles, cells in the surrounding normal tissues are not sensitive to radiotherapy due to the quiescent phase of cell division and only suffer minor damage. Meanwhile, the normal tissues around the tumor may be exposed to a sharp drop in the amount of radiation due to the low radioactive activity of particles, thus reducing the damage to the surrounding small intestine, blood vessels, and other pipelines. This low-dose, long-lasting radioactive source is more likely to damage tumor cells and inhibit tumor growth (
). Patients with pancreatic cancer often have intractable acute pain in the lower back or abdomen caused by tumor compression or invasion of the abdominal plexus, which can be prevented through the application of radioactive particles treatment, thus playing a better analgesic effect. This has been confirmed by the partial relief or disappearance of pain in patients in this study, and the quality of life of patients has also been improved. As per NCCN guidelines, the goal of radiation therapy is to prevent or delay local progression that may result in pain and local obstructive symptoms for locally advanced pancreatic cancer. The clinical outcome from the LAP 07 trial showed no additional overall survival benefit for chemoradiation therapy (CRT) compared to chemotherapy alone. However, health-related quality of life data during CRT supported the use of gemcitabine-based chemoradiation (
). The high expression of the multidrug resistance genes in pancreatic cancer cells makes pancreatic cancer less sensitive to chemotherapy. Currently, gemcitabine-based chemotherapy is considered to be the first-line standard treatment for advanced pancreatic cancer, but the response rate of systemic intravenous chemotherapy for gemcitabine alone is only 5%–10% (
). The chemotherapy was performed through arterial infusion, and there were no obvious complications of biliary tract infection. Indeed, gemcitabine resulted in improved overall survival compared with other chemotherapeutic agents in patients with bile duct cancer and unresectable pancreatic cancer. The reason for this was that gemcitabine had a synergistic effect that can significantly inhibit pancreatic cancer cells, mainly through G1 cycle arrest and through induction of apoptosis (
). There also was evidence of antitumor activity of cisplatin in advanced pancreatic carcinoma. In a Phase II study reported by Wils et al., 33 assessable patients were treated with single-agent cisplatin at a dose of 100 mg/m2. The response rate was 21%. The median duration of response was 5 months (
). Cisplatin works by forming DNA-DNA cross-links and DNA-protein cross-links; one of the mechanisms of resistance to cisplatin is thought to be the excision repair of the platinum-DNA adduct (
Efficient nucleotide excision repair of cisplatin, oxaliplatin, and Bis-aceto-ammine-dichloro-cyclohexylamine-platinum(IV) (JM216) platinum intrastrand DNA diadducts.
). Several clinical trials for the combination of gemcitabine and cisplatin have been conducted by researchers. The overall response rate in patients was 11%, 26%, 31%, and 31%, respectively. The median overall survival was 8.2–9.6 months (
). It can be seen that the combination of gemcitabine and cisplatin appears to have a better therapeutic effect than single-agent. And as mentioned earlier, health-related quality of life data during CRT supported the use of gemcitabine-based chemoradiation (
). Therefore, this combination therapy was also adopted in this study. Although the bilirubin of this group of patients decreased significantly after biliary drainage, the digestive system damage caused by pancreatic cancer and obstructive jaundice, such as gastrointestinal motility and digestive dysfunction, still existed. Therefore, injecting all chemotherapeutic drugs into the gastroduodenal artery or the common hepatic artery (for patients with liver metastasis) can reduce chemotherapeutic drugs entering the intestinal tract, thereby reducing gastrointestinal adverse reactions and increasing patient tolerance.
Perioperative brachytherapy has been applied in both radical and palliative treatment of pancreatic cancer, such as low dose rate (LDR) permanent implants (Iodine-125 seeds) and high dose rate (HDR) temporary implants (Iridium-192) (
). In a previous study conducted at Silesian Medical University, eight patients with pancreatic head cancer underwent palliative operations with the use of an original technique of catheter implantation for HDR-Ir192 brachytherapy. In the brachytherapy performed group, the mean survival time was 6.7 months (
). In the present study (Fig. 3), the median stent patency of the patients was 12.50 months (95% CI: 10.26, 14.74), and the median survival was 13.20 months (95% CI: 10.96, 15.44), with overall survival of 5.2–23.3 months. These improved clinical outcomes were related to the role of radioactive particles in tumor brachytherapy. In recent years, different centers have made constant efforts toward this direction with the use of radiotherapy and multiple drugs to improve the benefit of the treatment of locally advanced pancreatic head cancer (
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.
Prospective study of cetuximab and gemcitabine in combination with radiation therapy: feasibility and efficacy in locally advanced pancreatic head cancer.
Standardized thresholds of volume-based PET/CT parameters predicting survival of patients with pancreatic head cancer treated with stereotactic body radiation therapy.
). The corresponding trial data was listed for comparison in terms of survival and safety (Table 4). After the chemotherapy with gemcitabine and cisplatin, no adverse reaction of Grade Ⅲ ∼ Ⅳ occurred in all cases. Percutaneous 125I seed implantation combined with insertion of radioactive strips through the biliary stent has the characteristics of less trauma, fewer complications, simple operation, and so on. Better efficacy was achieved with this novel combination for the treatment of unresectable pancreatic head cancer.
Fig. 3Kaplan-Meier statistical analysis of stent patency (a) and overall survival (b).
In conclusion, our pilot study shows the technical effectiveness and safety of using this novel combination of percutaneous stenting with iodine-125 seed implantation and chemotherapy for the treatment of pancreatic head cancer with obstructive jaundice. In addition, with remission of obstructive jaundice combined with the increased survival, the outcomes indicate that patients with biliary obstruction benefited from the use of the treatment combination. Its long-term efficacy needs to be confirmed by further multicenter, large sample size prospective randomized controlled studies.
Pathologic stage of prostatic ductal adenocarcinoma at radical prostatectomy: effect of percentage of the ductal component and associated grade of acinar adenocarcinoma.
Efficient nucleotide excision repair of cisplatin, oxaliplatin, and Bis-aceto-ammine-dichloro-cyclohexylamine-platinum(IV) (JM216) platinum intrastrand DNA diadducts.
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.
Prospective study of cetuximab and gemcitabine in combination with radiation therapy: feasibility and efficacy in locally advanced pancreatic head cancer.
Standardized thresholds of volume-based PET/CT parameters predicting survival of patients with pancreatic head cancer treated with stereotactic body radiation therapy.
Financial support: This study was supported by the Construction Project of Fujian Province Minimally Invasive Medical Center (no. 2104517) and Fujian Province Health and Family Planning Commission (2016-CX-24).
Conflict of interest: No conflict of interest exists in the submission of this manuscript, and this manuscript is approved by all authors for publication. I would like to declare on behalf of my coauthors that the work described was original research that has not been published previously, and not under consideration for publication elsewhere, in whole or in part. All the authors listed have approved the manuscript that is enclosed.
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