Pancreatic cancer is the second most common gastrointestinal cancer and the fourth leading cause of cancer deaths in the United States (1999 statistic); however, only 10% to 20% of patients present with resectable disease. Approximately 30% to 40% of patients are diagnosed with locally advanced pancreatic cancer, and 50% have distant metastases. For these patients, palliative management that provides symptomatic relief of intestinal obstruction, pain, and jaundice is essential to improve quality of life. Intratumoral injections under computed tomography (CT) or ultrasound guidance represent innovative strategies for delivering chemotherapeutic agents, that avoid the side effects associated with systemic chemotherapy. According to the 2014 National Comprehensive Cancer Network guideline, gemcitabine plus cisplatin is recommended as a first-line treatment for nonresectable pancreatic cancer. Fibrin glue is an adherent hemostat that can slow the release of high concentrations of anticancer drugs, including gemcitabine and cisplatin, to cancer cells.[7,8] In a nude mouse model, gemcitabine plus cisplatin mixed with fibrin glue obviously reduced the volume of orthotopically implanted pancreatic neoplasms. Here, we present a case series of patients with pancreatic cancer who received a CT-guided percutaneous intratumoral injection of gemcitabine plus cisplatin mixed with fibrin glue. Outcomes included prolonged overall survival, good local control, and pain relief.
2 Materials and methods
2.1 Patient description and diagnosis
Five patients diagnosed with unresectable poorly differentiated pancreatic ductal adenocarcinoma by intraoperative frozen biopsy (Patient 1) or percutaneous biopsy (Patients 2–5) were included in this study. All patients had refused chemotherapy but presented at our hospital for pain and jaundice relief (Table 1). The study was approved by the West China Hospital ethics committee, and all patients provided written informed consent. All patients underwent preoperative enhanced CT/magnetic resonance imaging (MRI), to evaluate the best puncture routine (Fig. 1A and B).
2.2 Solution preparation
COL solution: 30-mg cisplatin (Jiangsu Hansoh Pharmaceutical Co Ltd, China) was dissolved in 2-mL iohexol (Omnipaque; GE Healthcare, Co, Ltd, China) and 2-mL 2% lidocaine. Solution A consists of fibrinogen and factor XIII dissolved in aprotinin solution (1.5 mL). Solution B consists of thrombin mixed with calcium chloride solution (1.5 mL). Solution C consists of gemcitabine (600 mg, Jiangsu Hansoh Pharmaceutical Co) dissolved in Solution B.
Patients were placed in the prone or supine position and administered a local anesthetic (2% lidocaine, Shanghai Zhpharma Co, Ltd, China). The radiologist carefully inserted an 8-cm, 25-gauge needle into the tumor. Step I: COL solution (1 –2 mL) was injected into the tumor; the distribution of the COL solution in the tumor was carefully evaluated. Step II: 0.5 to 1 mL of Solution A was injected into the tumor followed by 1 mL of solution C. Subsequently, step I and step II were repeated (Fig. 1C and D). All procedures were guided by CT. Four patients (patients 2–5) with liver metastasis underwent conventional transartery chemoemboliztion (TACE) with 1000 mg/m2 gemcitabine plus 100 mg/m2 cisplatin mixed with lipiodol, 2 to 7 days after the previous procedures.
2.4 Statistical analyses
Data were analyzed using SPSS 19.0 (SPSS Inc, Chicago, IL). Continuous variables are summarized as means and standard deviations. The differences in numerical variables before and after treatment were evaluated using the paired t test. Ranked data, including the Visual Analogue Scale pain score (VAS), were compared using the rank-sum test. All statistical tests were 2-sided, and P < .05 was considered statistically significant.
This study included 5 patients that attended the Department of Abdominal Oncology, West China Hospital between April 2015 and January 2017. Baseline demographic and clinical characteristics of the patients are detailed in Table 1. Patient mean age was 60.2 ± 6.99 years, 2 patients were male, 3 patients were female, and 4 patients were suffering from liver metastases. Patient 2 had undergone gastroduodenectomy and cholecystotomy 3 months before the study.
Patient perioperative data are shown in Table 2. Among all patients, the mean number of intratumoral injections and TACE procedures were 1.5 ± 0.89 and 1.2 ± 0.84, respectively. Overall mean survival was16.2 ± 3.7 months. Local control rates were 100% and 80% at postoperative 3 and 6 months, respectively (Fig. 1Eand F). Mean VAS pain score decreased from 7.2 ± 0.84 preoperatively to 2.0 ± 1.22 by postoperative week 4. Patient 1 experienced obvious relief from jaundice on postoperative day 2. Based on CT or MRI evaluation, and according to the Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1), 3 patients showed complete response, 1 patient showed partial response, and 1 patient had stable disease at postoperative 1 month. There were no significant differences in pre- and postoperative carbohydrate antigen 19–9, carbohydrate antigen, or carcinoembryonic antigen levels.
No adverse events, such as emesis or serious pain, were observed during the procedures. There were no procedures associated patient side-effects such as fever, gastrointestinal bleeding, or acute pancreatitis. Patients 1, 2, and 4 did not experience any postoperative adverse events. Postoperatively, patient 3 experienced grade 2 emesis (3 episodes in 24 hours), which spontaneously resolved within 24 hours. Patient 5 also experienced grade 2 emesis (4 episodes in 24 h), which spontaneously resolved in 48 hours. Patient 3 experienced ascites 6 months postoperatively, owing to disease progression.
For patients with unresectable pancreatic cancer, current chemotherapies have negligible survival benefits as pancreatic carcinomas have concentration- and time-dependent sensitivity to locoregional chemotherapy.[9,10] Therefore, the development of effective and minimally invasive strategies that selectively deliver antitumor drugs to the tumor site, release high concentrations of antitumor drugs for extended periods of time, and minimize distribution of antitumor drugs throughout the body remains an unmet need.
In the current case series of patients treated with CT-guided percutaneous intratumoral injection of gemcitabine plus cisplatin mixed with fibrin glue, mean overall survival was 16.2 ± 3.7 months, and the patients reported substantial pain relief. A search of the PubMed database from January 1990 to December 2016, revealed that case reports or case series focused on intratumoral drug administration in pancreatic cancer are scarce (Table S1, http://links.lww.com/MD/B858). However, the findings from the current case series are in accordance with previously published studies. Chang et al reported a median survival of 13.2 months in a Phase I clinical trial of 8 pancreatic cancer patients treated with a single injection of cytoimplant immunotherapy by endoscopic ultrasound (EUS)-guided fine-needle injection. Hanna et al reported that 7 pancreatic cancer patients survived ≥6 months and 2 patients survived ≥12 months, following 2 weeks of twice weekly CT- or EUS-guided BC-819 intratumoral injections. Schad et al investigated intratumoral mistletoe (Viscum album L) therapy in patients with unresectable pancreatic carcinoma. The median survival of patients at stages III and IV were 11.8 months and 8.3 months, respectively. Hecht et al reported a phase I/II trial of EUS-guided ONYX-015 intratumoral injection, in which 21 patients with locally advanced adenocarcinoma of the pancreas or metastatic disease achieved a median survival of 7.5 months. In a Phase I trial, Endo et al found that preoperative EUS-guided fine-needle injection of immature dendritic cells with OK-432 in pancreatic cancer patients (n = 9) undergoing resection resulted in a median survival of 1.5 years, compared to 1.4 years in patients operated without immature dendritic cell injection (n = 15). Jin et al reported a case study on pancreatic cancer, where EUS-guided celiac ganglion radiofrequency ablation reduced the VAS pain score from 8 to 2 in a 57-year-old male patient.
In this case series, the procedures administered to the patients were associated with some complications; however, all resolved spontaneously. There were no serious complications, such as acute pancreatitis or death, emphasizing the safety of this approach. The complication rate in the current case series was similar to that observed in previous studies.[15,12] Hanna et al reported asymptomatic elevation of lipase as an adverse event in their trial of twice weekly CT- or EUS-guided BC-819 intratumoral injections in pancreatic cancer patients. Endo et al noted 1 transient grade 3 fever among their pancreatic cancer patients, following preoperative EUS-guided fine-needle injection of immature dendritic cells with OK-432.
Fibrin glue is a water-insoluble gel matrix that is formed when fibrinogen is activated by thrombin in the presence of Ca2+ and factor XIII. Evidence suggests that fibrin glue is an effective therapeutic tool for slowing the release of drugs, including antibiotics, growth factors, and chemotherapeutic agents, at a local site.[8,18,19] Sugitachi et al reported that release of adriamycin or cisplatin from a fibrin clot was sustained over 15 days in cancer bearing rats. Fbrin clot-adriamycin/cisplatin-treated rats survived >200 days and the tumors disappeared. In comparison, rats treated with adriamycin/cisplatin injected intraperitoneally died within 20 days. In a nude mouse model, Ogura et al demonstrated that the concentration of gemcitabine in the pancreas in mice treated with a mixture of gemcitabine and fibrin glue, that adhered to the pancreatic tail, was 10-fold higher than mice treated with an intraperitoneal injection. Furthermore, the growth of orthotopically implanted pancreatic neoplasms was decreased by 62% compared to control mice. Median survival time of mice in the control, fibrin glue group, and gemcitabine and fibrin glue group was 44, 48, and 57 days, respectively.
This study was limited by its small sample size; however, the findings suggest that gemcitabine plus cisplatin mixed with fibrin glue administered by CT-guided percutaneous intratumoral injection has potential as a safe and effective approach to decrease pain and improve survival in patients with advanced unresectable pancreatic cancer.
The authors acknowledge the support of The National Nature Science Foundation of China (81470141). The authors thank MinLan Yuan for reviewing this manuscript.
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