Pain Palliation by Endoscopic Ultrasound-Guided Celiac Plexus Neurolysis in Patients with Unresectable Pancreatic Cancer

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1 Pain Palliation by Endoscopic Ultrasound-Guided Celiac Plexus Neurolysis in Patients with Unresectable Pancreatic Cancer Andrada Seicean 1,2, Calin Cainap 3, Iulia Gulei 2, Marcel Tantau 1,2, Radu Seicean 4 1) 3rd Medical Clinic University of Medicine and Pharmacy Iuliu Hatieganu 2) Regional Institute of Gastroenterology and Hepatology 3) Oncological Institute Ion Chiricuta 4) First Surgical Clinic, University of Medicine and Pharmacy Iuliu Hatieganu Cluj-Napoca, Romania Address for correspondence: Andrada Seicean, MD, PhD Regional Institute of Gastroenterology and Hepatology Croitorilor street 19-21, Cluj-Napoca, Romania andradaseicean@yahoo.com ABSTRACT Background: Endoscopic ultrasound-guided celiac plexus neurolysis (EUS-CPN) represents an alternative approach to pain palliation in patients with advanced pancreatic cancer. Aim: to evaluate the safety and initial efficacy of EUS-CPN in patients with painful unresectable pancreatic cancer. Methods: Patients with inoperable body-tail pancreatic adenocarcinoma without prior chemotherapy and pain requiring opioid analgesia were included prospectively in this cohort study in a tertiary medical center. Central EUS-CPN was performed and the brief pain inventory and the Functional Assessment of Cancer Therapy measurement were applied before and 2 weeks after the procedure. Results: Thirty-two patients underwent the procedure in one session without complications. Follow-up revealed overall pain relief in 24 patients (75%) and significant improvement in pain scores. Ratings of pain interfering with general activity, walking, work, mood, enjoyment of life, relations with others, and sleep improved significantly. Physical, functional, and emotional well-being improved significantly, except for acceptance of illness and enjoyment of life. Conclusion: Central EUS-CPN was an efficient and safe method for palliative pain management in our patients with inoperable pancreatic body-tail adenocarcinoma. The pain alleviation improved the patients functional status, sleep, and quality of life, although other variables could also be involved, but acceptance of the illness and enjoyment of life did not change after treatment. Key words: endosonography celiac plexus pancreatic neoplasm pain evaluation autonomic nerve blocks. Received: Accepted: INTRODUCTION Pancreatic cancer has the worst prognosis of all cancers due to the difficulty of early diagnosis and its aggressive evolution. It is the fifth leading cause of cancerrelated death in the world, and up to 90% of the patients with advanced disease present pain. Pancreatic cancer pain is not only visceral; it also has a neuropathic component which is very difficult to treat with standard analgesic medication. To achieve a better quality of life for the patient, the present recommendation for pain management proposes a ladder approach, starting with non-steroidal anti-inflammatory drugs, followed by escalating doses of opioids as needed [1]. Adequate therapy often requires treatment with high doses of opiate-based analgesics, which can be complicated by intolerable adverse effects such as drowsiness, delirium, dry mouth, anorexia, constipation, nausea and vomiting, and an analgesic ceiling due to neurotoxicity. Although the current recommendation does not state a maximum dose for opioid medication, in clinical practice adverse effects can cause serious problems. Moreover, persistent pain may even be associated with decreased survival in patients with pancreatic cancer [2, 3]. Therefore, methods entailing destruction of pain pathways by means of alcohol injection are promising options for pain relief and reduction of the risk of drug-induced adverse effects. Alcohol can be administered transcutaneously, endoscopically with ultrasound guidance, or surgically. The posterior transcutaneous approach (guided by ultrasound or CT) was associated with good pain relief in 70 to 90% of patients until death, but serious complications such as paraplegia, paresthesia, and pneumothorax were noted in 1% of patients [4, 5]. The anterior approach using endoscopic ultrasoundguided celiac plexus neurolysis (EUS-CPN) has the advantage of providing the most direct access and better visualization of the celiac region, with fine orientation of the injection

2 60 Seicean et al needle above (central approach) or lateral to the celiac trunk (bilateral approach), directly into the celiac ganglia or over the superior mesenteric artery [6], thus avoiding neurological complications. Only few complications have been reported with this method: postural hypotension, diarrhea, transient pain exacerbation, or retroperitoneal abscess [7]. To date, there are conflicting reports concerning the utility of celiac plexus neurolysis in terms of pain alleviation [8-11], improvement of quality of life, or even survival [12, 13]. The aim of this study was to evaluate the safety and initial efficacy of EUS-CPN in terms of pain relief and quality of life in patients with painful unresectable adenocarcinoma of the body or tail of the pancreas. MATERIAL AND METHODS This was a prospective study of patients undergoing EUS- CPN for local advanced pancreatic adenocarcinoma. All the included patients had inoperable pancreatic body-tail cancer without prior chemotherapy and presented pain necessitating opioid analgesia. All the patients included in the study were in stage 3 of major opioid analgesia: after an initial titration period with i.v. administration, they were switched to oral administration of breakthrough pain doses (at 1/6 to 1/10 of the total daily dosage). Patients were enrolled in the study if their visual analog scale (VAS) pain score was >3 (moderate or severe pain) at the time of endoscopy and a diagnosis of cancer was confirmed by cytopathologic examination. These criteria were selected on the basis of published data showing that 85% of patients with VAS >30 mm have a moderate pain and 85% with VAS >50 mm have severe pain [14]. Patients presenting celiac plexus compression by tumor or lymph nodes were excluded from the study, as were those with coagulation problems (INR >1.5 or platelet count <50,000/μl), those with tumor in the head of the pancreas, those with cancer therapy other than painkillers, and those who were unable to complete the assessment tools. The study was approved by the authors institutional ethics committee and complied with the principles outlined in the Declaration of Helsinki. All patients provided written informed consent for the procedures performed and for their inclusion in this study. Protocol of EUS-guided neurolysis All procedures were conducted with the patient in left lateral position under either general anesthesia with propofol or intravenous deep sedation with 2-4 mg midazolam, according to the patient s preference. If the patient was found to have unresectable disease and the fine-needle aspiration findings were consistent with pancreatic cancer, CPN was performed under EUS guidance using a therapeutic linear-array echo-endoscope (GF-UCT 140 AL5, Olympus) after color Doppler assessment for vessel-gut interposition. All procedures were performed by a single endosonographer. The injection needle (22-gauge, Olympus) was placed into the targeted central position, advanced to the celiac trunk, and 10 ml bupivacaine 1% was injected. A single injection of ml absolute alcohol was then administered, causing a dense hyperechoic cloud in the area of injection and spilling around to the periganglionic space (Fig. 1). Fig. 1. The position of the needle during endoscopic ultrasound-guided celiac plexus neurolysis. The origin of the celiac trunk and the superior mesenteric artery from aorta are seen. The needle (black arrow) is inserted at celiac plexus just above origin of celiac trunk from aorta. Above the celiac trunk the cloudy aspect of alcohol injected is visible (white arrow). All patients were kept under close observation for 2 h after the procedure to monitor blood pressure, heart rate, and temperature and to identify any immediate complications such as hypotension, tachycardia, pain enhancement, and paraplegia. The patients were called 48h after the procedure to monitor for late side effects such as diarrhea, hypotension, fever, and paraplegia. Assessment of pain and quality of life Before the procedure, the Brief Pain Inventory-Short Form (BPI; validated in the national language) [15] and the Functional Assessment of Cancer Therapy - General version 4 (FACT-G) [16, 17] were administered to each patient, the global health score was assessed by VAS (0-100), and the analgesic medication used was recorded. The first part of the BPI questionnaire evaluated the presence of pain, using a VAS from 0 to 10 (0 = no pain and 10 = worst pain imaginable) to report average pain (for previous 7 days), minimum and maximum pain, and response to painkillers. Following the ESMO 2011 guideline [18], a VAS score of 4-6 was considered to represent moderate pain and a score 7 was taken to indicate severe pain. The rest of the BPI described the relationship of pain with activities such as working, walking, sleeping, social relations, and enjoyment of life. The FACT-G questionnaire evaluated physical well-being, social/family well-being, emotional wellbeing, and functional well-being. The patient s present health status was assessed by means of a VAS (0-100). Follow-up Pain and quality of life were re-evaluated when the patient returned 2 weeks after EUS-CPN. The BPI and FACT-G were administered again, and any change in opioid daily dosage was recorded. Pain improvement was defined as a drop of 2 points in pain score compared with the index value without a concurrent increase in oral opioid intake. Statistical analysis Patient demographics and treatment characteristics such as age, gender, tumor size and location, pain intensity, and opioid use at presentation were summarized as counts and percentages or mean, standard deviation, median, and range. Pain scores at baseline and at 2 weeks were compared by the

3 Celiac plexus neurolysis in pancreatic cancer 61 paired Student t-test or Wilcoxon signed rank test, according to normality of data. The chi-square test or the Fisher exact test were used to compare therapy response rates at 2 weeks by potential predictors, using the SPSS statistical package (SPSS, Chicago, Ill.). These potential predictors included visualization of tumor location, tumor size, and pain location. RESULTS A total of 35 patients were enrolled in the study between January 2008 and May Three patients could not be contacted within 2 weeks for follow-up and were excluded from the final analysis. The remaining 32 patients were 56.93±9.5 years old (range 37-68), with a male:female ratio of 22:10. Only four patients had tumors located exclusively in the tail of the pancreas. The pain was located in the epigastrium in 8 patients (25%), in the back in 6 patients (18.75%), in both the epigastrium and the back in 16 patients (50%), and in other locations in 2 patients (6.25%).The median tumor size was 3.5 cm (2.5-5). All of the patients had histologically confirmed adenocarcinoma. Only one session of EUS-CPN was performed in each case. No complications or side effects were noted. Initial pain was moderate in 20 patients (62.5%) and severe in 12 patients (37.5%). After EUS-CPN, the average pain decreased by 1 point in 2 patients, by 2 points in 12 patients, by 3 points in 4 patients, by 4 points in 10 patients, and by 5 points in 2 patients. The average pain increased in intensity in 2 patients. Overall, average pain decreased significantly by 2 points or more in 28 of 32 patients (87.5%) (p=0.001) and the worst pain also decreased significantly (p=0.001). Two of the four patients who had been taking major analgetics gave up their opioid medication, and the two patients who showed no response to the procedure increased the dose of major painkillers. The pain relief provided by medication after EUS- CPN was 90%, not significantly different from the 80% pain relief induced by medication before the procedure (Table I). Physical, emotional, and functional well-being scores were improved after the procedure (Table II, III). Family and social support did not change after EUS-CPN. The VAS global health score increased from 40±17.22 to 65±12.14 (p=0.003). Exclusive location of the tumor in the tail of the pancreas (p=0.43), the location of pain (p=0.99), and the size of the tumor (p=0.44) were not important for pain response. DISCUSSION Pancreatic ductal adenocarcinoma is a highly aggressive tumor. Because pain is the principal symptom and the majority of pancreatic cancers are detected in an advanced stage with no possibility of curative treatment, the palliation of pain has become a central preoccupation for many researchers. Chemical or destructive methods of interrupting the pain pathway are promising in this respect. The utility of EUS-CPN in unresectable pancreatic cancer has been studied by several authors (Table IV), and two metaanalyses showed an alleviation rate of around 80% [9-10], with a duration of about 4-5 weeks. In our study, the rate of pain alleviation, defined as a decrease of 2 points in pain score, in short-term follow-up was 75%, similar to other results [7, 19, 20] and superior to that obtained in a study in which a rate of only 45% alleviation was found after 7 days of follow-up [21]. Pain alleviation using the easier central technique seemed inferior to that obtained by bilateral injection [9], although a recent randomized study Table I. Pain intensity before and after endoscopic ultrasound-guided celiac plexus neurolysis (Brief Pain Inventory, scale of 1 to 10) Pain intensity (n=32) Before procedure (min-max) After procedure (min-max) Worst pain 9±1.21 (6-10) 5±1.93( 2-10) Medium pain 6±1.03 (4-7) 3±1.13 (2-6) Least pain 1.5±1.83(0-5) 0± 0.81 (0-3) Current pain 4.5±2.4 (0-7) 2±1.94 (0-6) Percentage of complete pain relief provided by medication SD, standard deviation 80±22.21 (40-100) 90±15.4 (50-100) 0.19 p Table II. Parameters of interference with pain before and after endoscopic ultrasound-guided celiac plexus neurolysis (Brief Pain Inventory, scale 1 to 10) Parameters of interference (n=32) Before procedure After procedure General activity 7.75±2.17 5± Walking 4.56± ± Work 7.94± ± Mood 7.25± ± Enjoyment of life 7.69± ± Relations with others 5.31± ± Sleep 8.19± ± p

4 62 Seicean et al Table III. Results of Functional Assessment of Cancer Therapy General quality of life questionnaire (score 1 to 10) before and after endoscopic ultrasound-guided celiac plexus neurolysis Parameters of interference Physical well-being Before procedure After procedure Lack of energy a 3±0.82 2± Nausea a 1±1.21 1± Trouble meeting needs of family a 3±1.04 2± Pain a Bothered by side effects a 3±0.47 2± Illness perception a 1±1.14 1± Spending time in bed a 3±0.83 2± Social/familial well-being 2.5±1.41 2±1.49 Closeness to friends 3±0.93 3± Emotional support from family 4±0.7 4± Support from friends 3±0.83 3± Accepting illness (family) 4±0.63 4± Family communication 4±0.63 4± Closeness to partner 4±0.72 4± Content with sex life NA NA NA Emotional well-being Saddness a 3±0.68 1± Coping with illness 2±0.85 3± Loosing hope a 1±1.61 1± Nervousness a 1.5±1.29 1± Worry about dying a 3±1.18 1± Worry about worsening 3±1.43 1± condition a Functional well-being Work capability 1±1.02 2± Fulfilling work 1± ± Enjoying life 2±1.25 2± Accepted illness (patient) 3±1.07 3± Sleeping 1±0.68 3± Enjoying leisure activities 0.5±0.87 1± Content with quality of life 1±0.92 2± a Reverse score item; NA: not avaible p showed no difference between these two procedures [21] (Table IV). We excluded tumors of the pancreatic head, in which the response seems better, perhaps because the tumors are less advanced [1] or the pain is due to distension of the biliary tree. Also, because it had previously been shown that the pain during natural course is initially viscerally determined, via the celiac plexus, and somatic or other neuropathic pathways are involved later [22], we included only patients who were naïve for chemotherapy or surgery. This study was the first to evaluate the efficacy of EUS-CPN in pain alleviation by using a complex pain score. It showed that average pain and worst pain had decreased significantly by 2 weeks after the procedure, but complete relief using painkillers was not significantly different, although some patients gave up their morphine-based medication. All BPI measures of the effects of pain showed significant improvement after EUS- CPN, including walking, general activity, working, sleeping, and enjoyment of life. The FACT-G quality of life questionnaire showed that physical, functional, and emotional well-being improved significantly after EUS-CPN, as well as the subjective appreciation of quality of life. Functional status, work capability, sleeping, and enjoyment of leisure activities improved significantly. Difficulties in physical status such as lack of energy, poor physical condition, and feeling ill were ameliorated. The need to stay in bed and the side effects due to medication, though lower, were not significantly different. Social and family support did not differ before and after EUS-CPN, but feelings of sadness and

5 Celiac plexus neurolysis in pancreatic cancer 63 Table IV. Pain relief and techniques used in patients with endoscopic ultrasound- guided celiac plexus neurolysis Reference No of patients Pain evaluation Technique of EUS-CPN Follow-up period (weeks) Pain alleviation Wyse et al 2011 [12] 48 Likert scale Bilateral % LeBlanc et al 2011[13] 50 Numeric rating scale Unilateral vs bilateral vs 81% Iwata et al 2011 [17] 47 Visual analogue scale Unilateral 1 68,1% Ascunce et al 2011 [1] 64 Numeric rating scale Ganglia or bilateral 1 50% Sakamoto et al 2010 [6] 67 Visual analogue scale Under celiac trunk % Sahai et al 2009 [19] 160 Visual analogue scale Unilateral versus bilateral 1 70 vs 45% Ramirez-Luna et al 2008 [18] 10 Visual analogue scale Unilateral % Levy et al 2008 [24] 17 General descriptors Ganglia 4 94% Tran et al 2006 [25] 10 Numeric rating scale Unilateral Not stated 70% Gunaratnam et al 2001 [7] 58 Visual analogue scale Bilateral 24 78% Wiersema et al 1996 [26] 30 Visual analogue scale Bilateral % worries about worsening of the condition or death diminished after the procedure. No differences were found, however, for coping with the disease (hopefulness and satisfaction with one s own behavior), acceptance of the disease, enjoyment of life, or fulfillment at work. The main limitations of this study are the small number of patients, the short period of follow-up and the lack of a control group. However, we focused on tumors of the body and tail of the pancreas, which are less responsive to pain treatment, and we excluded patients with celiac plexus compression by tumor or lymph nodes and those receiving any cancer therapy other than painkillers. Also, only patients with moderate or severe pain were included. The Brief Pain Inventory has not previously been used for assessment of the efficacy of EUS-CPN. The Functional Assessment of Cancer Therapy instrument, used previously for assessment of the effect of postoperative and postpalliative treatment in pancreatic cancer [17, 23-25], showed that the quality of life and the health score improved significantly after the procedure, although this has not been confirmed in other studies [12]. CONCLUSIONS Central EUS-CPN seems to be an efficient and safe method for short-term pain management in patients with inoperable pancreatic body-tail cancer. Although functional status, sleep, and the quality of life were improved by diminishing pain, the patients acceptance of the disease and enjoyment of life did not change. Conflicts of interest: None to declare. Acknowledgements: The authors are grateful to Teodora Mocan for assistance with the biostatistical analysis. REFERENCES 1. Ascunce G, Ribeiro A, Reis I, et al. 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