Clinical Study Endoscopic Ultrasound-Guided Celiac Plexus Neurolysis in Pancreatic Cancer : A Prospective Pilot Study of Safety Using 10 mL versus 20 mL Alcohol

1Division of Gastroenterology and Hepatology, Indiana University Medical Center, 550 North University Boulevard, UH 4100, Indianapolis, IN 46202, USA 2Department of Adult Health, School of Nursing, Indiana University, Indianapolis, IN 46202, USA 3Department of Biostatistics, School of Medicine, Indiana University, 410 W. Tenth Sreet, Suite 3000, Indianapolis, IN 46202-3012, USA 4 School of Medicine, Indiana University, Indianapolis, IN 46202-3082, USA 5Regenstrief Institute, Indianapolis, IN, USA 6Houston VA Health Services Research & Development Center of Excellence, Indianapolis, IN, USA


Introduction
One of the main concerns of patients with pancreatic cancer is pain [1].For patients with pancreatic cancer, pain has a negative impact on quality of life (HRQoL) [2].Pain will be present in a third of patients at the time of diagnosis, 30% to 50% undergoing treatment, and up to 90% with advanced disease [3][4][5][6][7][8][9][10]. Aer surgery for pancreatic cancer from 60% to 84% of patients reported moderate-to-severe pain [11].While opioids are commonly used to relieve pain, their adverse side effects such as sedation, constipation, nausea, and vomiting have a negative impact on quality of life [3].Celiac plexus neurolysis is not associated with these adverse effects and may improve survival among unresectable pancreatic cancer patients [5].Although endoscopic ultrasound-guided celiac plexus neurolysis (EUS-CPN) does not have the side effects of opioids, it is not free of risks [12,13].Acute spinal cord infarction has been reported aer EUS-CPN [13].
e amount of alcohol used in EUS-CPN ranges from 2 to 20 mL of alcohol [14][15][16][17][18]. ere are no randomized studies that compare the safety of varying amounts of alcohol in celiac plexus neurolysis.We hypothesized that 20 mL of alcohol was safe in EUS-CPN.Onset of HRQoL and survival were also examined.

Methods
is study was approved by the Institutional Review Board at Indiana University Medical Center.Consecutive patients with known or suspected unresectable pancreatic cancer and pain were enrolled.Written informed consent to participate in this study was obtained from all patients enrolled.Patients were excluded if they had the following: previous CPN (endoscopic or percutaneous), an implanted pain relieving device, or an arterial abdominal aneurysm.Patients were selected to receive 20 mL of 0.75% bupivacaine followed by 10 mL or 20 mL of alcohol for EUS-CPN.Opioid use was not a prerequisite for entry into this study.Pain relief was de�ned as a pain score less than or equal to 4, or at least a 30% decrease in the pain score compared to baseline pain without an increase in pain medication usage.
2.1.EUS-CPN Procedure.EUS-CPN is de�ned as injection of a neurolytic agent into the celiac plexus area or directly into celiac ganglia.Aer providing informed consent, subjects were sedated with intravenous fentanyl, midazolam, and/or Propofol.A 22-gauge hollow Echotip Ultra needle (Cook Medical, Winston-Salem, NC, USA) was passed through the working channel of the echoendoscope, through the posterior wall of the stomach and directly into the celiac ganglia (Figures 1(a) and 1(b)) when visualized or anterior to the celiac trunk.A 5 mL sterile saline-�lled syringe was loaded onto the needle and was used to "test" the position of the needle tip.rough the needle 20 mL of 0.75% bupivacaine was injected followed by 10 mL or 20 mL of 98% alcohol.If celiac ganglia were visualized, they were directly injected until the ganglia borders were blurred.When celiac ganglia were not sonographically identi�ed, the needle was targeted to the origin of the celiac artery takeoff within 2 to 3 mm.e medication is administered in the same sequential fashion.Aer the EUS-CPN procedure, each patient was observed for at least one hour in the recovery room.Each patient received 1000 mL of intravenous �uids and antibiotics.Oral antibiotics were prescribed for three days.Prior to discharge each patient was assessed by the physician.

Followup.
Baseline pain medication use and pain scores were documented for each patient.Each patient was called at 24 hours and weekly by a blinded research coordinator.Followup continued until the patient reported a return of their pain to baseline or died.Patients rated pain using a numeric rating scale (NRS) that ranges from 0 to 10 where 0 is "no pain" and 10 is "worst pain." During each phone interview, patients were also asked to quantify their use of pain medications.During each phone interview, the subject's pain was assessed using the brief pain inventory (BPI).e BPI is a three question survey that rates intensity of pain (severity) and interference of pain with mood, physical activity, work, social activity, relations with others, sleep, and enjoyment of life [19,20].Two HRQoL instruments, EORTC QLQ-30 and EORTC PAN-26, were administered during phone interviews at baseline, week 2, week 4, and every 4 weeks thereaer until the subject reported a return of their pain to baseline or died.e date of death was documented for each subject.

Statistical
Methods.e frequency of complications was calculated.Complete response was de�ned as a pain score of zero without an increase in pain medication usage.Kaplan-Meier estimates of duration of pain relief were calculated.
Health-related quality of life (HRQoL) scores were summarized for each patient.Patients who died while still experiencing pain relief are censored from our calculation of pain-free survival.Patients who did not achieve pain relief within the �rst four weeks of followup are assigned zero for duration of pain relief and were not be censored.e overall survival is calculated from the time of EUS-CPN.

Results
Patient characteristics are demonstrated in Table 1.e characteristics of pain relief in each group are demonstrated in Table 2.Among patients who received adjuvant chemotherapy and/or radiation, the median (range) duration of pain relief was 2.6 (0-32) weeks.Among patients who did not receive adjuvant chemotherapy and/or radiation the median (range) duration of pain relief was 2 (0-32) weeks.Pain scores are shown in  deaths during the phone interview followup period of this study.Among the 10 patients who had direct injection of celiac ganglia, the median (range) duration of pain relief was 3 (0-32) and 3 (2-30) weeks for the 10 mL and 20 mL groups, respectively, ( = 0.69).In patients who did not have direct injection of celiac ganglia, the median (range) duration of pain relief 3 (2-8) and 1 (1-14) for the 10 mL and 20 mL alcohol groups, respectively, ( = 0.19).A Kaplan Meier survival curve is shown in Figure 2.

Discussion
ere were no major complications seen with the 20 mL of 98% alcohol group compared to the 10 mL group.During the EUS-CPN procedure all patients received a combination of fentanyl, versed, and propofol for sedation which likely explains the absence of pain in the recovery room.We found that EUS-CPN with 20 mL of alcohol compared to 10 mL of alcohol was safe.However, we also noted that clinical outcomes of the two groups were similar with respect to overall pain relief (100% in 20 mL group versus 80% in 10 mL group), weekly pain scores, onset of pain relief, duration of pain relief, and proportion of complete responders.is suggests that 20 mL alcohol during EUS-CPN may not provide signi�cant pain relief despite its safety.A statistically signi�cant difference is not observed between the two groups, however, as our study was a pilot study.A larger prospective study is warranted to con�rm our �ndings.We also noted an equal number of complete responders in each group.Two thirds of these complete responders in each group had direct injection of celiac ganglia.is suggests that direct visualization and injection of celiac ganglia may improve the accuracy of EUS-CPN.e overall efficacy, however, of EUS-CPN is likely explained by the diffuse spread of alcohol in the celiac region which likely explains this result.
With respect to pancreatic pain, digestive symptoms, nausea, and vomiting, relatively better HRQoL scores were seen in the 20 mL group.is �nding has not previously been reported, and a larger prospective study is necessary for con�rmation.ere is a subtle trend in improved survival in the 20 mL group.Survival in general may be related to pain relief and may re�ect the patient�s ability to perform daily activities of living and have better nutrition.A larger  prospective study, however, is necessary to con�rm these observations.
It has been reported that patients with pancreatic cancer have lower pain scores and pain medication consumption up to 16 weeks aer EUS-CPN [15,21].In 2006 the precise identi�cation and injection of celiac ganglia during EUS-CPN were reported in 16 of 22 (73%) patients [22].In 2008 efficacy and safety of directly injected celiac ganglia during EUS-CPN were reported in 17 patients with unresectable pancreatic cancer and pain [16].At 2 and 4 weeks, 94% of subjects reported pain relief as "complete, " or "partial" [16].Likewise, percutaneous and intraoperative celiac plexus neurolysis (CPN) have been performed with varying concentrations (50% to 100%) and amounts (15 to 50 mL) Median (range) duration of pain relief (weeks) of alcohol [23][24][25][26][27] with efficacy ranging from 70% to 90% [23].e variable response rates may be attributed to lack of targeted injection into ganglia [5,23,26,[28][29][30].In a recent meta-analysis of percutaneous CPN, pain relief was rated as good to excellent in 89% aer 2 weeks, partial to complete in 90% at 3 months, and partial to complete in 70-90% at the time of death [23].
In our study minor self-limited postprocedure adverse effects were seen in a third of subjects including transient lightheadedness, diarrhea, nausea, and vomiting.Our experience is similar to previous reports of adverse effects including diarrhea (17%), postural hypotension (1%), and postprocedure-related abdominal pain (9%) [14,31].In a report by Levy and colleagues, 7 of 17 patients (36%) experienced pain exacerbation in the recovery room which lasted 2.2 days [16].Procedure-related transient abdominal pain was noted in 9% of subjects who did not have direct injection of celiac ganglia [14].ere have been 2 reports of major complications occurring aer EUS-CPB using steroids for chronic pancreatitis including death aer an arterial pseudoaneurysm hemorrhage [32], and a peripancreatic abscess developed 5 days aer EUS-CPB treated with intravenous antibiotics [33].A recent report of acute spinal cord infarction following EUS-CPN was attributed to 24 mL of a 1 : 5 mixture of bupivacaine 0.25% with epinephrine and alcohol (5 mL into a celiac ganglia, and 19 mL into the celiac trunk area) [13].In this patient with pancreatic adenocarcinoma of the head, the procedure resulted in paraplegia.is incident lends to support that targeted injection of the celiac ganglia is preferred, as the spinal artery can be injured during EUS-CPN.
Lillemoe and colleagues demonstrated improved survival aer intraoperative CPN (20 mL of 50% alcohol) in a doubleblinded randomized placebocontrolled study of 139 subjects with unresectable pancreatic cancer [5].A survival bene�t was not seen, however, with percutaneous CPN (20 mL 100% alcohol) in patients with unresectable pancreatic cancer [26].
e main limitation of our study is the size.In our pilot study we have demonstrated preliminary evidence that EUS-CPN 20 mL 98% alcohol appears safe.Injection of ganglia appears to improve accuracy of EUS-CPN and possibly the duration of pain relief.A larger prospective trial is warranted to con�rm our �ndings and further understandhow to examine the potential predictors of adjuvant therapy (chemotherapy, radiation, or both) and direct ganglia injection (versus injection into the celiac region) on the clinical outcomes of pain relief, quality of life, and survival.

F 2 :
Survival in subjects by randomization.e survival curve shows the length of survival in days from the EUS-CPN procedure.e slashed line represents subjects in the 20 mL alcohol group, and the straight line represents subjects in the 10 mL alcohol group.

Table 3
. Four of 20 (20%) subjects (2 in each group) had pain relief that lasted over 16 weeks.Characteristics of complete responders (patients who had complete pain relief) are shown in Table4.ere were no Diagnostic and erapeutic Endoscopy 3 T 2: Characteristics of pain relief.
Life.HRQoL at the week 4 of followup is shown in Table5.Scores directly correlated with pain relief on multiple measures.Minor adverse effects seen in the 10 mL group included transient diarrhea in 1 and lightheadedness in 1. Minor adverse effects seen in the 20 mL group included transient diarrhea in 5 and nausea and vomiting in 1.
ere were no complications of bleeding or paralysis.
T 3: Pain scores over time.
T 5: Quality of life scores at 4 weeks.