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Palliative Therapy for Pancreatic Cancer
PANCREATIC CANCER
1055-3207/98 $8.00
+ O. O
PALLIATIVE THERAPY FOR PANCREATIC CANCER Keith D. Lillemoe, MD
Cancer of the pancreas is the fourth leading cause of cancer death in the United States.41Although significant progress has been made in the last decade with respect to both operative results and long-term survival in patients resected with a curative intent, the overall picture for this disease remains grim. Less than 20% of affected patients survive 1 year after diagnosis, and the overall 5-year survival rate is less than 5%.28Because only the minority of patients are resectable for cure at the time of presentation, palliation of symptoms to maximize the quality of life is of primary importance in most patients. Palliation for pancreatic cancer is directed primarily at three symptoms: obstructive jaundice, duodenal obstruction, and pain. As with resectional therapy, advances have been made over the last decade in the management of these problems. Currently, both surgical and nonoperative techniques are available to provide optimal palliation of symptoms. The management of most patients with pancreatic cancer therefore can be tailored to best suit the individual patient's clinical presentation, prognosis, and overall medical condition. OBSTRUCTIVE JAUNDICE
Most pancreatic cancers arise in the head of the pancreas; thus, obstructive jaundice is the most common presenting symptom. Jaundice is present at the time of diagnosis in approximately 70% of patient^.^^,^^ If untreated, obstructive jaundice results in progressive liver dysfunction and culminates in liver failure and early death. In addition, the pruritus associated with obstructive jaundice can be unbearable and seldom responds to medications. Finally, the jaundiced patient usually experiences anorexia, nausea, and progressive malnutrition. Therefore, relief of jaundice may provide dramatic, albeit short-term, improvement in the patient's overall well-being. In a review of more than 8000 patients reported in the English literature from 1965 to 1980, Sarr and Cameron35found that biliary From the Department of Surgery, The Johns Hopkins Medical Institutions, Baltimore, Maryland SURGICAL ONCOLOGY CLINICS OF NORTH AMERICA VOLUME 7 - NUMBER 1 -JANUARY 1998
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bypass was associated with a longer and more comfortable survival (5.4 months) when compared with patients undergoing only diagnostic laparotomy (3.5months). An attempt to palliate obstructive jaundice is indicated in almost all but the most terminal patient. Fortunately, obstructive jaundice is the most amenable of the symptoms of pancreatic cancer to nonoperative techniques. Biliary decompression can be achieved either by endoscopic or radiologic methods in almost all patients. Surgical relief of jaundice can be reserved for those selected patients who are either better operative candidates or have longer projected survival.
Nonsurgical Palliation of Obstructive Jaundice
Percutaneous transhepatic external drainage of the obstructed biliary tree was first performed in the mid-1970s with subsequent modification to allow internal drainage. By the 1980s, the use of endoscopically placed biliary endoprosthesis had become common. Initially, in both techniques, the stents were small and associated with a high incidence of clogging, with resultant recurrent jaundice and cholangitis. A number of modifications in the last decade have resulted in both larger silastic stents and metallic stents that are more resistant to late obstruction (Fig. 1). In addition, both techniques may be used for preoperative biliary decompression of the jaundiced patient before surgical exploration for resection or palliation. The percutaneous transhepatic approach for biliary drainage is often technically easy to accomplish because of the significant intrahepatic biliary ductal dila-
Figure 1. Cholangiogram demonstrating a self-expanding metallic endoprosthesisplaced for
palliation of unresectable pancreatic cancer.
PALLIATIVE THERAPY FOR PANCREATIC CANCER
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tation. The procedure is generally performed under local anesthesia with intravenous sedation; however, most patients do require hospitalization. After accessing the biliary tree, a guidewire is placed into the extrahepatic ductal system and through the obstruction. In some patients, the procedure may be staged to allow a period of external drainage to minimize the risk of cholangitis associated with the initial procedure. After several days of external drainage, the small catheter can be exchanged fluoroscopically for either a larger stent with external access or a completely internalized plastic or metallic endoprosthesis. In cases in which external access is maintained, the catheter should be increased progressively in size and eventually exchanged as an outpatient procedure on a 3-month basis to prevent cholangitis and recurrent jaundice secondary to clogging. Self-expanding metallic endoprostheses have gained recent popularity because of their low incidence of late o c c l ~ s i o n . ~ , ~ ~ The success rate for obtaining external drainage with an obstructed biliary system approaches 100%.The percentage of patients in whom complete internal drainage can be accomplished is generally less, in the range of 85%.Complications include bleeding; therefore, correction of any pre-existing coagulopathy, bile leakage, pneumothorax, pleural effusion, pancreatitis, and cholangitis is essential. All patients should receive prophylactic antibiotics before and for a short period of time after each procedure. The endoscopic approach offers two distinct advantages over the percutaneous technique. First, endoscopic examination may visualize the tumor mass and allow biopsy to obtain a tissue diagnosis. Second, in the evaluation of the etiology of obstructive jaundice, a pancreatogram can be obtained, which may provide useful information. After endoscopic examination, a limited sphincterotomy is performed, and a small catheter that contains an atraumatic guidewire is passed into the bile duct and maneuvered through the stricture. Then, over this catheter, a large endoprosthesis is positioned through the obstruction. At least a 10 F endoprosthesis with hooks to secure its position and prevent migration should be used (Fig. 2). The success rate for endoscopic endoprosthesis placement is approximately 90%. Cholangitis and pancreatitis are the most common complications, with cholangitis usually following failed or inappropriate stent placement. The small sphincterotomy seldom results in significant bleeding or perforation. The mean length of long-term stent patency for most prostheses is approximately 3 to 6 months. Recently, metallic expandable prostheses also have been used by way of the endoscopic route in hopes of providing longer stent patency (see Fig. 1),9,30,31
A review has been published by Watanapa and W i l l i a m ~ o nof~ ~the recent developments in the palliation of pancreatic cancer. This analysis of series published between 1981 and 1990 has summarized the results of the percutaneous and endoscopic techniques used for palliation of malignant biliary obstruction (Table 1). These studies have demonstrated that nonoperative palliation by either the percutaneous or endoscopic route can be obtained successfully in more than 90% of patients with minimal morbidity and mortality. Endoscopic stenting appears to be associated with a shorter initial hospital stay. One randomized, prospective trial that compared the percutaneous and endoscopic methods for palliation of obstructive jaundice has been published.40Seventy patients were entered into the study performed at The Middlesex Hospital in London between 1983 and 1985. The success rate for relief of jaundice was 81% by way of the endoscopic approach and only 61% by way of the percutaneous route. Furthermore, the procedure-related mortality for the percutaneous approach was 36% versus 13% for the endoscopic technique, and the overall complication rate was 67% with the percutaneous versus only 19%for the endoscopic technique. Overall, this trial and the nonrandomized studies reviewed suggest
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Figure 2. Cholangiogram demonstrating a silastic endoprosthesis with hooks to secure the position and prevent migration.
that the endoscopic approach is preferable, with percutaneous drainage reserved only for those patients in whom endoscopic access is not possible. All previous comparative studies have used plastic prosthetic stents; therefore, late complications due to stent obstruction are common (Table 1).Preliminary results from a prospective randomized trial of endoscopically placed self-expanding metallic stents (Wallstent) versus polyethylene (10-F) stents for malignant ~ stent placement was acbiliary obstruction have been r e p ~ r t e d .Successful complished in an equal percentage of patients with similar procedure-related morbidity and 30-day mortality. The median stent patency of the Wallstent was 273 days versus 154 days with the polyethylene stent. This difference, at the preliminary point of data analysis, had not yet reached statistical significance. This technique offers promise for optimizing nonoperative palliation for patients with malignant biliary obstruction.
Surgical Biliary Bypass Surgical options for palliation of obstructive jaundice include internal biliary bypass by means of a choledochoduodenostomy, cholecystojejunostomy, or hepatico-(cho1edocho)-jejunostomy.External biliary drainage by way of a surgicallyplaced T-tube can relieve jaundice effectively. However, this procedure creates an external biliary fistula that often drains large volumes of bile and results in severe fluid and electrolyte imbalance. Therefore, simple external drainage should not be considered an option. Anastomosis of the gallbladder to the stomach also has been used and was used in the early reports of surgical palliation of pancreatic
Table 1. COMPARATIVE RESULTS BETWEEN PERCUTANEOUS AND ENDOSCOPIC STENT PLACEMENT AND SURGICAL BYPASS IN PATIENTS WITH MALIGNANT OBSTRUCTION OF THE COMMON BILE DUCT Percutaneous Stent ( n = 490)
30-day mortality (%) hospital stay (days) success rate (%) early complications (%) late complications (%)
Endoscopic Stent ( n = 689)
Surgical Bypass ( n = 1807)
Range
Mean
Range
Mean
Range
Mean
6-33 13-1 8 76-1 00 4-67 7-38
9 14 92 16 28
0-20 3-26 82-1 00 8-34 1345
14 7 90 21 28
0-3 1 9-30 75-1 00 6-56 5-47
12 17 93 31 16
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cancer. The disadvantages of this technique, including bile gastritis, acid hypersecretion secondary to gastrin release, and food entry into the biliary tree, have led to its abandonment in most centers. A choledochoduodenostomy is generally not considered by most surgeons to be a suitable alternative for biliary bypass for pancreatic cancer due to concerns about recurrent jaundice secondary to duodenal obstruction. Furthermore, an anastomotic leak with this procedure is associated with leakage of both bile and gastroduodenal secretions. However, despite these concerns, Potts et aP2 at The Cleveland Clinic have performed this procedure routinely with good overall results. In this report, only 1 of 61 patients who underwent choledochoduodenostomy developed recurrent jaundice. Cholecystojejunostomyis advocated by many surgeons because it can be performed quickly and does not require dissection of the extrahepatic biliary tree. If the gallbladder is to be selected for biliary bypass, the surgeon must ensure that the cystic duct joins the common hepatic duct at least 2 to 3 cm from the tumor mass to prevent future obstruction. In most cases, this information can be provided by the preoperative cholangiogram; however, if a question exists, an operative cholecystogram may be performed. A hepaticojejunostomymust be performed in patients in whom the gallbladder is surgically absent or in whom the tumor approaches the cystic duct. A number of retrospective studies and collected reviews have compared the short-term and long-term results of cholecystojejunostomy and hepaticojejunostomy for palliation of obstructive jaundice. In the review by Sarr and Camer0n,3~ the operative mortality rate for cholecystojejunostomy was 16% versus 20% for hepaticojejunostomy. Long-term survival was also similar, being 6.5 months after hepaticojejunostomy and 5.3 months after cholecystojejunostomy. However, the incidence of recurrent jaundice was lower after hepaticojejunostomy (0%versus 8%).A more recent meta-analysis by Watanapa and W i l l i a m ~ o nfound ~ ~ that cholecystoenterostomy carried an 89% success rate, whereas that of choledochoenterostomy was 97%.Operative mortality rates were also similar. An important finding that emerged from that review, however, was that recurrent jaundice or cholangitis occurred in 20% of patients in whom the gallbladder was used for bypass. This question was addressed by a prospective, randomized trial in which cholecystoenteric bypass was compared with choledochoenterostomy.34Although this study included patients with benign and malignant disease, most patients in both groups had biliary obstruction due to pancreatic cancer. Although operative time and blood loss were significantly less in patients who underwent cholecystojejunostomy, significantly more major postoperative complications occurred in this group. Both operative deaths in the series occurred in patients who underwent cholecystoenterostomy. Finally, in long-term follow-up, late bypass failure occurred significantly more frequently in patients in whom the gallbladder was used. In eight of the nine failures, obstruction was due to progressive pancreatic carcinoma, with five bypasses failing within 90 days of operation. A final advantage of hepaticojejunostomy is that in many patients, early cholecystectomy and dividing the bile duct facilitates dissection and determination of resectability for pancreatic cancer. For all these reasons, the use of the bile duct for surgical biliary bypass is performed for most patients with pancreatic cancer. Comparative Results
The overall results for the surgical palliation of obstructive jaundice have been excellent, with successful relief of jaundice in more than 90% of patients (Table 1).
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Short-term morbidity and mortality and hospital stay are acceptable but generally are greater than with the nonoperative techniques. The major advantage for surgical bypass is the lower rate of late complications. In the last decade, four prospective studies have been completed in which surgical biliary bypass has been compared with nonoperative biliary stenting for malignant obstructive jaundice Patients were enrolled in these trials if they were considered fit (Table 2).2,6,12,37 for operation but unresectable for cure. Patients with endoscopic or clinical evidence of duodenal obstruction were excluded. In three of the four studies, endoscopic biliary stent placement was used primarily, whereas in the fourth study, a percutaneously placed transhepatic endoprosthesis was inserted. These studies suggest that surgical and nonoperative techniques are equally effective in short-term relief of jaundice. Endoscopic stenting, however, is associated with a lower procedure-related complication rate and a shorter overall period of hospitalization. Three of the four studies reported lower 30-day mortality rates in patients treated nonoperatively, but in none of these studies did the difference achieve statistical significance, presumably because of the relatively small number of patients involved. The combined data for the four studies indicate 30-day mortality rates of 11% for patients treated with nonoperative stenting compared with 18%in patients treated surgically. One criticism of these studies is that the surgical mortality rates are much higher than reported in several recent series from North Ameri~a.~~,~~,~~ The major concern in review of these studies is the long-term results in the nonoperatively managed patients. Recurrent jaundice is seen in 17 to 38% of stented patients and seldom occurs in surgically palliated patients. Although recurrent jaundice usually can be managed by endoscopic stent change, its association with cholangitis results in significant morbidity and mortality. Whether these problems will be resolved with the use of metallic expandable stents has yet to be answered completely. The final concern that usually cannot be addressed by the nonoperative techniques is duodenal obstruction. Although not present before randomization, the incidence of late duodenal obstruction in the nonsurgical arms of these studies ranges from 9 to 14%.In the surgically managed patients, duodenal obstruction rarely occurred. The management of this late problem, often particularly difficult in the patient with advanced disease, leads many surgeons to favor surgical biliary bypass. DUODENAL OBSTRUCTION
At the time of diagnosis, 30 to 50% of patients with pancreatic cancer note symptoms of nausea and v ~ m i t i n g . Actual ~ , ~ ~ ,mechanical ~~ obstruction of the duodenum, seen on radiographic or endoscopic examination, occurs much less frequently at the time of presentation (Fig. 3).3As unresectable disease progresses, however, duodenal obstruction occurs in a significant percentage of patients. Three series have assessed the role of late duodenal obstruction. In the review by Sarr and Cameron35of more than 8000 surgically managed patients reported in the literature, 13%of patients who did not undergo gastric bypass at their initial operation required a gastrojejunostomy before death. In addition, another 20% of the remaining patients died with symptoms of duodenal obstruction. In a review of more than 950 patients in the more recent literature by Singh and Reber,39the percentage who required a gastrojejunostomy at a later date was 21%. Finally, in ~ than 1600 cases, 17% (range the review by Watanapa and W i l l i a m ~ o nof~ more 4%-44%) of patients who underwent biliary bypass alone developed duodenal obstruction at a mean of 8.6 months later and required subsequent gastric bypass.
Table 2. RESULTS OF PROSPECTIVE, RANDOMIZED TRIALS OF NONOPERATIVE VERSUS SURGICAL PALLIATION FOR MALIGNANT BlLlARY OBSTRUCTION South Africa6
N % success complications (%) 30-day mortality (%) hospital stay (days)
United Kingdom"
Stent
Surgery
Stent
Surgery
25 84 28 8 18
25 76 32 20 24*
23 82 30 9 5
25 92 56 20 13t
Denmark2 Stent
Surgery
United Kingdom12 Stent
Surgery
late complications jaundice1 cholangitis (%) gastric outlet obstruction (%) survival fwks) 'Median postprocedural hospital stay was significantly shorter in stented patients; however, when readmissionsfor late complications were considered,asignificantdifference no longer existed. tBoth initial and total hospital days were less in the stented group. $13% required two admissions for late biliary complications. §Six patients randomized to surgical arm did not undergo surgical palliation. In one patient, extensive tumor precluded palliative bypass. Five other patients underwent endoscopic stent placement. Data presented are based on randomization.
PALLIATIVE THERAPY FOR PANCREATIC CANCER
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Figure 3. Upper gastrointestinal series demonstrating duodenal obstruction by a cancer located in the head of the pancreas.
In none of these reviews did performance of a gastrojejunostomy at the original operation increase the operative mortality. However, in patients who required a second operation, mortality rates are generally higher-approaching 25%.44The authors of all of these collected reviews, therefore, favor prophylactic gastrojejunostomy in patients who undergo laparotomy for unresectable pancreatic cancer. Despite the results of these collected reviews, significant controversy continues concerning the role of prophylactic gastrojejunostomy. A number of series have shown an increase in postoperative morbidity, primarily delayed gastric , ~ ~ , ~ ~et a145also have suggested that gasemptying with this p r ~ c e d u r e . " , ' ~Weaver trojejunostomy performed in the presence of duodenal obstruction is associated ~ , ~ results have led this with a high perioperative morbidity and m ~ r t a l i t y .These group to advocate antrectomy as the procedure of choice in the setting of duodenal obstr~ction.~~ Traditionally, most surgeons have recommended performing an antecolic gastrojejunostomy to avoid placement of the gastrojejunal anastomosis in the bed of the tumor. In the Johns Hopkins series;' a retrocolic gastrojejunostomy was used in 70% of 107 patients. A strong trend toward a decreased incidence of delayed postoperative gastric emptying (6% versus 17%,P = 0.08) was seen to favor the retrocolic position versus an antecolic gastrojejunostomy. Late gastric outlet
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obstruction occurred in only 2% of patients after retrocolic anastomosis compared with 9% with the antecolic procedure ( P = 0.16). Although concern for stoma1 ulceration remains, vagotomy is not justified because it may contribute further to delayed gastric emptying. The routine use of histamine (Hz)receptor antagonists prevents this complication in most patients. Recently attempts at nonoperative palliation of duodenal obstruction have These ~ , ~techniques ~,~~ involve endoluminal placement of larger (30 been r e p ~ r t e d . ~ mm in diameter, 60-90 mm in length) metallic stents through the area of duodenal obstruction. In some patients, combined endoscopic and percutaneous access by way of an endoscopic gastrostomy is necessary. Although current experience has been limited to small series and case reports, the preliminary results are encouraging, with most patients resuming enteral nutrition until death. PAIN
Perhaps the most disturbing and incapacitating symptom of pancreatic cancer is pain. Unfortunately, for many patients, this symptom is poorly managed and remains a significant problem until death. Depending on the location of the tumor, pain can be a common symptom at presentation. In past series, up to 90% of patients reported abdominal or back pain or both at the time of presentation.16 More recently, perhaps with a greater awareness of the diagnosis, the percentage of patients with pancreatic cancer presenting with pain has decreased. Recent studies have shown that only 30 to 40% of patients with pancreatic cancer report significant pain at the time of referral, with another 30% only having minimal Yet at the time of death, most patients with unresected complaints of pain.l7fZ1 pancreatic cancer experience significant pain. The use of intraoperative chemical splanchnicectomy for unresectable pancreatic cancer was first introduced by Copping et a18 in 1978. In their subsequent report of 41 patients in 1978, 88% of patients with pain due to pancreatic cancer experienced relief of pain postoperatively.14Most of these patients underwent palliative biliary and gastrointestinal bypass at the same operation. These patients were compared with a group of historical controls in whom 21% of patients had pain control after similar palliative procedures. No complications of chemical splanchnicectomy were reported. Since that time, other anecdotal studies describing successful control with chemical splanchnicectomy have appeared. In 1993, our group at Johns Hopkins reported the first prospective, randomized, placebo-controlled study of intraoperative chemical splanchnicectomy.21All patients who underwent exploration for pancreatic cancer underwent preoperative assessment of pain and quality of life using a visual analog scale. Randomization was performed at the time of operation, when the diagnosis of unresectable pancreatic carcinoma was confirmed. Chemical splanchnicectomy was performed by injection of either 20 cc of 50% alcohol or a saline placebo on each side of the aorta at the level of the celiac axis (Fig. 4). The hospital course was monitored for postoperative complications and length of hospital stay. After hospital discharge, the patient's pain management was directed entirely by the treating physician. Follow-up pain questionnaires were completed by direct interview or by mail for all patients at 2-month intervals until their death. A total of 139 patients underwent randomization, with 2 patients excluded from chemical splanchnicectomy because of extensive tumor in the area of the celiac axis. Sixty-five of the patients received 50%alcohol injection, and 72 patients received a saline placebo. No difference was observed in hospital mortality or complications, return to oral intake, or length of hospital stay. Mean pain scores were significantly lower in the alcohol group at 2-, 4-, and 6-month follow-up and
PALLIATIVE THERAPY FOR PANCREATIC CANCER
jOO/o
209
alcohr celiac
Figure 4. Chemical splanchnicectomy is performed using a syringe and a 20- or 22-gauge spinal needle. Alcohol (20 cc of 50%) is injected on each side of the aorta at the level of the celiac axis (IVC = inferior vena cava). (From Lillemoe KD, Cameron JL, Kaufman HS, et al: Chemical splanchnicectomy in patients with unresectable pancreatic cancer: A prospective randomized trial. Ann Surg 217:447, 1993; with permission.)
at the final assessment before patient's death (Fig. 5A). In patients without preoperative pain, alcohol significantly reduced pain scores and delayed or prevented the subsequent onset of pain. In patients with significant preoperative pain, alcohol significantly reduced existing pain (Fig.5B).Furthermore, although actuarial survival was similar between the two study groups, in the subgroup of patients with significant preoperative pain, a marked improvement in survival was obtained when compared with the saline placebo (Fig. 6). These two groups were analyzed with respect to age, tumor location, tumor stage, operation performed, the use of chemotherapy and radiation therapy, baseline mood, and disability. No significant difference was apparent for any of these factors. We concluded from this study that the routine use of intraoperative chemical splanchnicectomy with
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8.0 7.0
1
1Alcohol
1
0Saline
.
N=
A
65 72 PreOp
58 58 2 mos
N=
I3
0Saline
20
17
PreOp
29 25 6 mos
.
59 62 Final
*p < 0.05
Alcohol 7.0
41 43 4 mos
+p = 0.01
19
11
2 mos
10
5
4 mos
19
12
Final
Figure 5. A, Mean pain scores measured at the preoperative, 2-, 4-, and 6-month and final assessments for all randomized patients surviving at each point. B, Mean pain scores measured at the preoperative, 2- and 4-month, and final assessments for all patients with significant preoperative pain surviving at each point. (From Lillemoe KD, Cameron JL, Kaufman HS, et al: Chemical splanchnicectomy in patients with unresectable pancreatic cancer: A prospective randomized trial. Ann Surg 217:447, 1993; with permission.)
PALLIATIVE THERAPY FOR PANCREATIC CANCER
-Alcohol pain (n
=
20)
Saline pain (n
=
14)
-----.
211
Months of Survival Figure 6. Kaplan-Meier survival curves determined from the time of hospital discharge for patients with significant preoperative pain. (From Lillemoe KD, Cameron JL, Kaufman HS, et al: Chemical splanchnicectomyin patients with unresectable pancreatic cancer:A prospective
randomized trial. Ann Surg 217:447, 1993;with permission.) alcohol should be performed in all patients who undergo laparotomy for unresectable pancreatic carcinoma. In patients who do not undergo laparotomy for pancreatic carcinoma, the appropriate use of oral agents can manage pain successfully in most patients. Patients with significant pain should receive their medication on a regular schedule and not on an as-needed basis. The use of long-acting morphine derivative compounds is best suited for such treatment. Two nonoperative treatment modalities may be used to manage intractable pain that does not respond to oral pain medication. The first major modality in pain control is percutaneous celiac nerve block performed with either fluoroscopic or CT guidance. Pain relief can be ob. ~ ~ second modality used tained in 80 to 90% of patients with this t e ~ h n i q u eThe for control of pain due to unresectable pancreatic cancer is external beam radiation therapy. Although uncontrolled, many series have shown a beneficial effect on pancreatic cancer pain in most patients. Most recently, thoroscopic splanchnicectomy and endoscopic chemical splanchnicectomy with the aid of ultrasound guidance have been introduced. However, whether these newer procedures will provide results equivalent to older techniques has yet to be determined. OVERALL RESULTS OF SURGICAL PALLIATION
Two major advantages exist for surgical palliation of pancreatic cancer. The first is the ability to combine adequate long-term palliation for all three primary symptoms of the disease. Only surgical management provides a single procedure that can relieve obstructive jaundice, treat or prevent duodenal obstruction, and reduce or prevent the significant pain associated with an unresectable tumor. The final major advantage for exploration of patients with pancreatic cancer is the potential for a curative resection. Although preoperative assessment with CT, cholangiography, visceral angiography, and laparoscopy can be valuable in the assessment of resectability, only thorough surgical exploration can rule out resect-
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ability in most patients. False acceptance of certain demise in all patients with pancreatic cancer, coupled with nonoperative palliation, denies a number of patients the opportunity for resection for cure. To justify the role of surgical palliation for pancreatic cancer, the overall results must be accomplished with acceptable morbidity and mortality. Fortunately, a number of recent series have provided excellent results with respect to perioperative morbidity and mortality, and long-term p a l l i a t i 0 n . ~ ~ ,In ~ ,the 3 ~ series , ~ ~ from Johns Hopkins of 118 patients found at surgery to have unresectable periampullary malignancy, surgical palliation was accomplished with a 2.5% hospital mortality rate.23Combined biliary bypass and gastrojejunostomy was performed in 75% of the patients. Although perioperative complications were frequent (occurring in 37% of patients), most were minor and seldom life threatening. The mean hospital stay was only 14 days, with patients returningto a regular diet at a mean of approximately 10 days. The distribution for survival for the 118 patients is shown in Figure 7, with an overall mean survival being 7.7 months. Similar results have been obtained by other groups with hospital mortality rates between 2 and 4%.10,32
LAPAROSCOPIC PALLIATION OF PANCREATIC CANCER
As with almost all areas of surgery, the use of minimally invasive surgical techniques has been applied recently to the management of pancreatic cancer. The role of diagnostic laparoscopy for the staging of pancreatic neoplasms has been well e s t a b l i ~ h e d . The ~,~~ techniques ,~~ include not only visual inspection but also ultrasonographic assessment of major visceral vesselsz6and obtaining fluid for cytologic analysis. Recently, reports have described operative techniques and reported small series of patients undergoing palliation of biliary and duodenal obstruction with laparoscopic cholecystojejunostomy and gastrojejunostomy.15~27~33
0
1-2
3-5
6-8
9-11
12-17
18-23
24+
Months Figure 7. Distribution of survival for 118 patients with unresectable periampullary carcinoma.
(From Lillemoe KD, Sauter PK, Pitt HA, et al: Current status of surgical palliation of periampullary carcinoma. Surg Gynecol Obstet, 176:1, 1993;with permission.)
PALLIATIVE THERAPY FOR PANCREATIC CANCER
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The results, although preliminary with respect to the number of patients reported, generally have shown technical success, low morbidity, and satisfactory outcomes. Whether these results can be extended to larger numbers of patients and into the hands of surgeons who are not at centers of laparoscopic surgical excellence has yet to be determined. PALLIATIVE PANCREATICODUODENECTOMY
Traditionally, pancreatic resection for cancer of the pancreas has been reserved only for patients in whom a potential for cure exists. The high morbidity and mortality associated with pancreaticoduodenectomy in the past has made this procedure inappropriate in patients when residual local disease or metastases precludes the chance for long-term cure. In the last decade, significant improvements have been noted in the perioperative morbidity and mortality for pancreaticodu~denectomy.~,'~,~~ Although the long-term results of surgical palliation are satisfactory, pancreaticoduodenectomy has potential benefits as a palliative procedure for pancreatic cancer. This role of pancreaticoduodenectomy in the palliation of pancreatic cancer was addressed recently in a retrospective comparison performed at the Johns Hopkins H o ~ p i t a lIn . ~this ~ study, 64 consecutive patients who underwent pancreaticoduodenectomy for pancreatic carcinoma with gross or microscopic evidence of adenocarcinoma at surgical resection margins were compared with 62 patients found to be unresectable at the time of laparotomy due to local invasion without evidence of metastatic disease. In the latter group, combined biliary and gastric bypass were performed for palliation in 87%of the patients. The two groups were similar with respect to age, gender, race, and presenting symptoms. The hospital mortality rate was identical for both groups at 1.6%.Fifty-eight percent of patients who underwent pancreaticoduodenectomy had an uncomplicated postoperative course compared with 68% of patients who underwent palliative bypass (not significant). The length of postoperative stay after pancreaticoduodenectomy was 18.4 days, which was significantly longer than for patients who underwent palliative bypass (15 days; P < 0.05). The overall actuarial survival (by Kaplan-Meier technique) was improved significantly in patients who underwent pancreaticoduodenectomy (P< 0.02) (Fig. 8).Postoperative chemotherapy and radiation therapy improved survival in both groups. Although this nonrandomized retrospective study can be criticized because of the questionable true compatibility of the two groups, the study does suggest that paIIiative pancreaticoduodenectorny, if performed with acceptably low perioperative morbidity and mortality, may offer some advantages to patients with seemingly unresectable disease. The incidence of rehospitalization after pancreaticoduodenectomy was 11%, whereas 20% of nonresected patients were readmitted to the hospital after their initial hospital discharge. Three of the nonresected patients required reoperation, whereas none of the patients who underwent pancreaticoduodenectomy required a subsequent operation. These differences were not significant as a comparison of quality of life. CONCLUSIONS
The decision to perform nonoperative versus surgical palliation for unresectable pancreatic cancer is influenced by a number of factors. In most cases, patient symptoms most clearly dictate the management. In patients with symptoms of
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-Palliative Pancreaticoduodenectomy
:.:!\..
- - - .- .
Palliative Bypass
... ....
p<0.02
Months Figure 8. Actuarial survival curves (Kaplan-Meier)for patients undergoing palliative pancreaticoduodenectomy (n = 64) and palliative bypass (n = 62). (From Lillemoe KD, Cameron JL, Yeo CJ, et al: Pancreaticoduodenectomy:Does it have a role in the palliation of pancreatic cancer? Ann Surg 223:718, 1996; with permission.)
duodenal obstruction at the time of presentation, surgery is the only option. In patients with obstructive jaundice alone, the options for management must be weighed against factors such as overall health status, projected survival, and procedure-related morbidity and mortality. A prospective multicenter trial recently analyzed factors that influence perioperative morbidity and mortality after pan. ~ analysis demonstrated that preoperative diabetes, low Kancreatic ~ u r g e r yThis ofsky's index, and liver metastases are significant risk factors in predicting perioperative morbidity and mortality in patients who undergo palliative procedures for pancreatic cancer. Another analysis that focused on tumor characteristicssuggests that for patients with stage I and stage I1 disease (i.e., with no evidence of systemic metastases), survival and the potential for late duodenal obstruction favor surgical management for these patient^.'^ In summary, although patient management must be individualized, most patients with pancreatic cancer who are in good medical health and have no evidence of systemicdisease are most appropriately managed with surgical palliation. This option affords them the best chance of avoidance of the late complications of recurrent jaundice, duodenal obstruction, and disabling pain. Surgical palliation generally can be completed with an acceptable perioperative morbidity and mortality as well as a hospital stay in the range of 2 weeks. Finally, only with surgical exploration can the opportunity for resection for cure be evaluated completely.
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References I . Adam A, Chetty N, Roddie M, et al: IS: Self-expandable stainless steel endoprostheses for treatment of malignant bile duct obstruction. AJR Am J Roentgen01 156:321, 1991 2. Andersen JR, Sorenson SM, Kruse A, et al: Randomized trial of endoscopic endoprosthesis versus operative bypass in malignant obstructive jaundice. Gut 30:1132, 1989 3. Andersson A, Bergdahl L: Carcinoma of the pancreas. Am Surg 42:173, 1976 4. Awad SS, Colletti L, Mulholland M, et al: Multimodality staging optimizes resectability in patients with pancreatic and ampullary cancer. Am Surg 63:634, 1997 5. Bakkevold KE, Kambestad B: Morbidity and mortality after radical and palliative pancreatic cancer surgery: Risk factors influencing the short-term results. Ann Surg 217:356, 1993 6. Bornman PC, Harries-Jones EP, Tobias R, et al: Prospective controlled trial of transhepatic biliary endoprosthesis versus biliary bypass surgery for incurable carcinoma of head of pancreas. Lancet i:69,1986 7. Cameron JL, Pitt HA, Yeo CJ, et al: One hundred and forty-five consecutive pancreaticoduodenectomies without mortality. Ann Surg 217:430, 1993 8. Copping J, Willix R, Kraft R: Palliative chemical splanchnicectomy. Arch Surg 113:509, 1978 9. Davids PHP, Fockens P, Groen AK, et al: A prospective trial of self-expanding metal stents vs polyethylene stents for malignant biliary obstruction: Preliminary results. Gastrointest Endosc 38:249, 1992 10. de Rooij PD, Rogatko A, Brennan MF: Evaluation of palliative surgical procedures in unresectable pancreatic cancer. Br J Surg 78:1053,1991 11. Doberneck RC, Berndt GA: Delayed gastric emptying after palliative gastrojejunostomy for carcinoma of the pancreas. Arch Surg 122:827,1987 12. Dowsett JF, Russell RCG, Hatfield ARW, et al: Malignant obstructive jaundice: A prospective randomized trial of by-pass surgery versus endoscopic stenting. Gastroenterology 96:128A, 1989 13. Fernandez-del Castillo C, Rattner DW, Warshaw AL: Standards for pancreatic resection in the 1990s. Arch Surg 130:295, 1995 14. Flanigan DP, Kraft RO: Continuing experience with palliative chemical splanchnicectomy. Arch Surg 113:509,1978 15. Fletcher DR, Jones RM: Laparoscopic cholecystjejunostomy as palliation for obstructive jaundice in inoperable carcinoma of the pancreas. Surg Endosc 6:147, 1992 16. Howard JM, Jordan GG: Cancer of the pancreas. Curr Probl Cancer 2:1,1977 17. Hudis C, Kelsen D, Niedzwieck D, et al: Pain is not a prominent symptom in most patients with early pancreas cancer. Proc Am Soc Clin Oncol10:326,1991 18. Jacobs PPM, van der Sluis, Wobbes T: Role of gastroenterostomy in the palliative surgical treatment of pancreatic cancer. J Surg Oncol42:145,1989 19. Keymling M, Wagner JH, Vakil N, et al: Relief of malignant duodenal obstruction by percutaneous insertion of a metal stent. Am J Gastroenterol39:439, 1993 20. Lichtenstein DR, Carr-Locke DL: Endoscopic palliation for unresectable pancreatic carcinoma. Surg Clin North Am 75:969,1995 21. Lillemoe KD, Cameron JL, Kaufman HS, et al: Chemical splanchnicectomy in patients with unresectable pancreatic cancer: A prospective randomized trial. Ann Surg 217:447, 1993 22. Lillemoe KD, Cameron JL, Yeo CJ, et al: Pancreaticoduodenectomy: Does it have a role in the palliation of pancreatic cancer? Ann Surg 223:718,1996 23. Lillemoe KD, Sauter PK, Pitt HA, et al: Current status of surgical palliation of periampullary carcinoma. Surg Gynecol Obstet 176:1, 1993 24. Lucas CE, Ledgerwood AM, Bender JS: Antrectomy with gastrojejunostomy for unresectable pancreatic cancer-causing duodenal obstruction. Surgery 110:583, 1991 25. Maetani I, Ogawa S, Hoshi H, et al: Self-expanding metal stents for palliative treatment of malignant biliary and duodenal stenoses. Endoscopy 26:701,1994 26. Murugiah M, Paterson-Brown S, Windsor JA, et al: Early experience of laparoscopic ultrasonography in the management of pancreatic carcinoma. Surg Endosc 7:177,1993 27. Nathanson LK: Laparoscopy and pancreatic cancer: Biopsy, staging and bypass. Baillieres Clin Gastroenterol7:941,1993 -
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28. National Cancer Institute: Annual cancer statistics review 1973-1988. Bethesda, MD, Department of Health and Human Services, 1991, publication no. 91-2789 29. Neuberger TJ, Wade TP, Swope TJ, et al: Palliative operations for pancreatic cancer in the hospitals of the U.S. Department of Veterans Affairs from 1987 to 1991. Am J Surg 166:632,1993 30. Neuhaus H, Hagenmuller F, Griebel M, et al: Percutaneous cholangioscopic or transpapillary insertion of self-expanding biliary metal stents. Gastrointest Endosc 37:31,1991 31. O'Brien S, Hatfield ARW, Craig PI, et al: A three year follow up of self expanding metal stents in the endoscopic palliation of longterm survivors with malignant biliary obstruction. Gut 36:618, 1995 32. Potts JR, Broughan TA, Hermann RE: Palliative operations for pancreatic carcinoma. Am J Surg 159:72,1990 33. Rhodes M, Nathanson L, Fielding G: Laparoscopic biliary and gastric bypass: A useful adjunct in the treatment of carcinoma of the pancreas. Gut 36:778,1995 34. Sarfeh IJ, Rypins EB, Jakowatz JG, et al: A prospective, randomized clinical investigation of cholecystoenterostomy and choledochoenterostomy. Am J Surg 155:411,1988 35. Sarr MG, Cameron JL: Surgical management of unresectable carcinoma of the pancreas. Surgery 91:123,1983 36. Sharfman WH, Walsh TD: Has the analgesic efficacy of neurolytic celiac plexus block been demonstrated in pancreatic cancer pain? Pain 41:267,1990 37. Shepard HA, Royle G, Ross APR, et al: Endoscopic biliary endoprosthesis in the palliation of malignant obstruction of the distal common bile duct: A randomized trial. Br J Surg 75:1166,1988 38. Singh SM, Longmire WP, Reber HA: Surgical palliation for pancreatic cancer: The UCLA Experience. Ann Surg 212:132,1990 39. Singh SM, Reber HA: Surgical palliation for pancreatic cancer. Surg Clin North Am 69:599, 1989 40. Speer AG, Cotton PB, Russell RCG, et al: Randomized trial of endoscopic versus percutaneous stent insertion in malignant obstructive jaundice. Lancet 2:57,1987 41. Steele GD, Osteen RT, Winchester DP, et al: Clinical highlights from the National Cancer Data Base: 1994. CA Cancer J Clin 44:71,1994 42. Warshaw AL, Gu ZY, Wittenberg J, et al: Preoperative staging and assessment of resectability of pancreatic cancer. Arch Surg 125:230,1990 43. Warshaw AL, Teper JE, Shipley WU: Laparoscopy in the staging and planning for pancreatic cancer. Am J Surg 151:76,1986 44. Watanapa P, Williamson RCN: Surgical palliation for pancreatic cancer: Developments during the past two decades. Br J Surg 79:8,1992 45. Weaver DW, Wiencek MD, Bouwman DL, et al: Gastrojejunostomy: Is it helpful for patients with pancreatic cancer? Surgery 102:608,1987 46. Yeo CJ, Cameron JL, Sohn TA, et al: 650 consecutive pancreaticoduodenectomies in the 1990s: Pathology, complications, outcomes. Ann Surg, 226:248, 1997
Address reprint requests to Keith D. Lillemoe, MD The Johns Hopkins Hospital 600 North Wolfe Street Blalock 679 Baltimore, MD 21287-4679
1055-3207/98 $8.00
+ O. O
PALLIATIVE THERAPY FOR PANCREATIC CANCER Keith D. Lillemoe, MD
Cancer of the pancreas is the fourth leading cause of cancer death in the United States.41Although significant progress has been made in the last decade with respect to both operative results and long-term survival in patients resected with a curative intent, the overall picture for this disease remains grim. Less than 20% of affected patients survive 1 year after diagnosis, and the overall 5-year survival rate is less than 5%.28Because only the minority of patients are resectable for cure at the time of presentation, palliation of symptoms to maximize the quality of life is of primary importance in most patients. Palliation for pancreatic cancer is directed primarily at three symptoms: obstructive jaundice, duodenal obstruction, and pain. As with resectional therapy, advances have been made over the last decade in the management of these problems. Currently, both surgical and nonoperative techniques are available to provide optimal palliation of symptoms. The management of most patients with pancreatic cancer therefore can be tailored to best suit the individual patient's clinical presentation, prognosis, and overall medical condition. OBSTRUCTIVE JAUNDICE
Most pancreatic cancers arise in the head of the pancreas; thus, obstructive jaundice is the most common presenting symptom. Jaundice is present at the time of diagnosis in approximately 70% of patient^.^^,^^ If untreated, obstructive jaundice results in progressive liver dysfunction and culminates in liver failure and early death. In addition, the pruritus associated with obstructive jaundice can be unbearable and seldom responds to medications. Finally, the jaundiced patient usually experiences anorexia, nausea, and progressive malnutrition. Therefore, relief of jaundice may provide dramatic, albeit short-term, improvement in the patient's overall well-being. In a review of more than 8000 patients reported in the English literature from 1965 to 1980, Sarr and Cameron35found that biliary From the Department of Surgery, The Johns Hopkins Medical Institutions, Baltimore, Maryland SURGICAL ONCOLOGY CLINICS OF NORTH AMERICA VOLUME 7 - NUMBER 1 -JANUARY 1998
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bypass was associated with a longer and more comfortable survival (5.4 months) when compared with patients undergoing only diagnostic laparotomy (3.5months). An attempt to palliate obstructive jaundice is indicated in almost all but the most terminal patient. Fortunately, obstructive jaundice is the most amenable of the symptoms of pancreatic cancer to nonoperative techniques. Biliary decompression can be achieved either by endoscopic or radiologic methods in almost all patients. Surgical relief of jaundice can be reserved for those selected patients who are either better operative candidates or have longer projected survival.
Nonsurgical Palliation of Obstructive Jaundice
Percutaneous transhepatic external drainage of the obstructed biliary tree was first performed in the mid-1970s with subsequent modification to allow internal drainage. By the 1980s, the use of endoscopically placed biliary endoprosthesis had become common. Initially, in both techniques, the stents were small and associated with a high incidence of clogging, with resultant recurrent jaundice and cholangitis. A number of modifications in the last decade have resulted in both larger silastic stents and metallic stents that are more resistant to late obstruction (Fig. 1). In addition, both techniques may be used for preoperative biliary decompression of the jaundiced patient before surgical exploration for resection or palliation. The percutaneous transhepatic approach for biliary drainage is often technically easy to accomplish because of the significant intrahepatic biliary ductal dila-
Figure 1. Cholangiogram demonstrating a self-expanding metallic endoprosthesisplaced for
palliation of unresectable pancreatic cancer.
PALLIATIVE THERAPY FOR PANCREATIC CANCER
201
tation. The procedure is generally performed under local anesthesia with intravenous sedation; however, most patients do require hospitalization. After accessing the biliary tree, a guidewire is placed into the extrahepatic ductal system and through the obstruction. In some patients, the procedure may be staged to allow a period of external drainage to minimize the risk of cholangitis associated with the initial procedure. After several days of external drainage, the small catheter can be exchanged fluoroscopically for either a larger stent with external access or a completely internalized plastic or metallic endoprosthesis. In cases in which external access is maintained, the catheter should be increased progressively in size and eventually exchanged as an outpatient procedure on a 3-month basis to prevent cholangitis and recurrent jaundice secondary to clogging. Self-expanding metallic endoprostheses have gained recent popularity because of their low incidence of late o c c l ~ s i o n . ~ , ~ ~ The success rate for obtaining external drainage with an obstructed biliary system approaches 100%.The percentage of patients in whom complete internal drainage can be accomplished is generally less, in the range of 85%.Complications include bleeding; therefore, correction of any pre-existing coagulopathy, bile leakage, pneumothorax, pleural effusion, pancreatitis, and cholangitis is essential. All patients should receive prophylactic antibiotics before and for a short period of time after each procedure. The endoscopic approach offers two distinct advantages over the percutaneous technique. First, endoscopic examination may visualize the tumor mass and allow biopsy to obtain a tissue diagnosis. Second, in the evaluation of the etiology of obstructive jaundice, a pancreatogram can be obtained, which may provide useful information. After endoscopic examination, a limited sphincterotomy is performed, and a small catheter that contains an atraumatic guidewire is passed into the bile duct and maneuvered through the stricture. Then, over this catheter, a large endoprosthesis is positioned through the obstruction. At least a 10 F endoprosthesis with hooks to secure its position and prevent migration should be used (Fig. 2). The success rate for endoscopic endoprosthesis placement is approximately 90%. Cholangitis and pancreatitis are the most common complications, with cholangitis usually following failed or inappropriate stent placement. The small sphincterotomy seldom results in significant bleeding or perforation. The mean length of long-term stent patency for most prostheses is approximately 3 to 6 months. Recently, metallic expandable prostheses also have been used by way of the endoscopic route in hopes of providing longer stent patency (see Fig. 1),9,30,31
A review has been published by Watanapa and W i l l i a m ~ o nof~ ~the recent developments in the palliation of pancreatic cancer. This analysis of series published between 1981 and 1990 has summarized the results of the percutaneous and endoscopic techniques used for palliation of malignant biliary obstruction (Table 1). These studies have demonstrated that nonoperative palliation by either the percutaneous or endoscopic route can be obtained successfully in more than 90% of patients with minimal morbidity and mortality. Endoscopic stenting appears to be associated with a shorter initial hospital stay. One randomized, prospective trial that compared the percutaneous and endoscopic methods for palliation of obstructive jaundice has been published.40Seventy patients were entered into the study performed at The Middlesex Hospital in London between 1983 and 1985. The success rate for relief of jaundice was 81% by way of the endoscopic approach and only 61% by way of the percutaneous route. Furthermore, the procedure-related mortality for the percutaneous approach was 36% versus 13% for the endoscopic technique, and the overall complication rate was 67% with the percutaneous versus only 19%for the endoscopic technique. Overall, this trial and the nonrandomized studies reviewed suggest
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Figure 2. Cholangiogram demonstrating a silastic endoprosthesis with hooks to secure the position and prevent migration.
that the endoscopic approach is preferable, with percutaneous drainage reserved only for those patients in whom endoscopic access is not possible. All previous comparative studies have used plastic prosthetic stents; therefore, late complications due to stent obstruction are common (Table 1).Preliminary results from a prospective randomized trial of endoscopically placed self-expanding metallic stents (Wallstent) versus polyethylene (10-F) stents for malignant ~ stent placement was acbiliary obstruction have been r e p ~ r t e d .Successful complished in an equal percentage of patients with similar procedure-related morbidity and 30-day mortality. The median stent patency of the Wallstent was 273 days versus 154 days with the polyethylene stent. This difference, at the preliminary point of data analysis, had not yet reached statistical significance. This technique offers promise for optimizing nonoperative palliation for patients with malignant biliary obstruction.
Surgical Biliary Bypass Surgical options for palliation of obstructive jaundice include internal biliary bypass by means of a choledochoduodenostomy, cholecystojejunostomy, or hepatico-(cho1edocho)-jejunostomy.External biliary drainage by way of a surgicallyplaced T-tube can relieve jaundice effectively. However, this procedure creates an external biliary fistula that often drains large volumes of bile and results in severe fluid and electrolyte imbalance. Therefore, simple external drainage should not be considered an option. Anastomosis of the gallbladder to the stomach also has been used and was used in the early reports of surgical palliation of pancreatic
Table 1. COMPARATIVE RESULTS BETWEEN PERCUTANEOUS AND ENDOSCOPIC STENT PLACEMENT AND SURGICAL BYPASS IN PATIENTS WITH MALIGNANT OBSTRUCTION OF THE COMMON BILE DUCT Percutaneous Stent ( n = 490)
30-day mortality (%) hospital stay (days) success rate (%) early complications (%) late complications (%)
Endoscopic Stent ( n = 689)
Surgical Bypass ( n = 1807)
Range
Mean
Range
Mean
Range
Mean
6-33 13-1 8 76-1 00 4-67 7-38
9 14 92 16 28
0-20 3-26 82-1 00 8-34 1345
14 7 90 21 28
0-3 1 9-30 75-1 00 6-56 5-47
12 17 93 31 16
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cancer. The disadvantages of this technique, including bile gastritis, acid hypersecretion secondary to gastrin release, and food entry into the biliary tree, have led to its abandonment in most centers. A choledochoduodenostomy is generally not considered by most surgeons to be a suitable alternative for biliary bypass for pancreatic cancer due to concerns about recurrent jaundice secondary to duodenal obstruction. Furthermore, an anastomotic leak with this procedure is associated with leakage of both bile and gastroduodenal secretions. However, despite these concerns, Potts et aP2 at The Cleveland Clinic have performed this procedure routinely with good overall results. In this report, only 1 of 61 patients who underwent choledochoduodenostomy developed recurrent jaundice. Cholecystojejunostomyis advocated by many surgeons because it can be performed quickly and does not require dissection of the extrahepatic biliary tree. If the gallbladder is to be selected for biliary bypass, the surgeon must ensure that the cystic duct joins the common hepatic duct at least 2 to 3 cm from the tumor mass to prevent future obstruction. In most cases, this information can be provided by the preoperative cholangiogram; however, if a question exists, an operative cholecystogram may be performed. A hepaticojejunostomymust be performed in patients in whom the gallbladder is surgically absent or in whom the tumor approaches the cystic duct. A number of retrospective studies and collected reviews have compared the short-term and long-term results of cholecystojejunostomy and hepaticojejunostomy for palliation of obstructive jaundice. In the review by Sarr and Camer0n,3~ the operative mortality rate for cholecystojejunostomy was 16% versus 20% for hepaticojejunostomy. Long-term survival was also similar, being 6.5 months after hepaticojejunostomy and 5.3 months after cholecystojejunostomy. However, the incidence of recurrent jaundice was lower after hepaticojejunostomy (0%versus 8%).A more recent meta-analysis by Watanapa and W i l l i a m ~ o nfound ~ ~ that cholecystoenterostomy carried an 89% success rate, whereas that of choledochoenterostomy was 97%.Operative mortality rates were also similar. An important finding that emerged from that review, however, was that recurrent jaundice or cholangitis occurred in 20% of patients in whom the gallbladder was used for bypass. This question was addressed by a prospective, randomized trial in which cholecystoenteric bypass was compared with choledochoenterostomy.34Although this study included patients with benign and malignant disease, most patients in both groups had biliary obstruction due to pancreatic cancer. Although operative time and blood loss were significantly less in patients who underwent cholecystojejunostomy, significantly more major postoperative complications occurred in this group. Both operative deaths in the series occurred in patients who underwent cholecystoenterostomy. Finally, in long-term follow-up, late bypass failure occurred significantly more frequently in patients in whom the gallbladder was used. In eight of the nine failures, obstruction was due to progressive pancreatic carcinoma, with five bypasses failing within 90 days of operation. A final advantage of hepaticojejunostomy is that in many patients, early cholecystectomy and dividing the bile duct facilitates dissection and determination of resectability for pancreatic cancer. For all these reasons, the use of the bile duct for surgical biliary bypass is performed for most patients with pancreatic cancer. Comparative Results
The overall results for the surgical palliation of obstructive jaundice have been excellent, with successful relief of jaundice in more than 90% of patients (Table 1).
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Short-term morbidity and mortality and hospital stay are acceptable but generally are greater than with the nonoperative techniques. The major advantage for surgical bypass is the lower rate of late complications. In the last decade, four prospective studies have been completed in which surgical biliary bypass has been compared with nonoperative biliary stenting for malignant obstructive jaundice Patients were enrolled in these trials if they were considered fit (Table 2).2,6,12,37 for operation but unresectable for cure. Patients with endoscopic or clinical evidence of duodenal obstruction were excluded. In three of the four studies, endoscopic biliary stent placement was used primarily, whereas in the fourth study, a percutaneously placed transhepatic endoprosthesis was inserted. These studies suggest that surgical and nonoperative techniques are equally effective in short-term relief of jaundice. Endoscopic stenting, however, is associated with a lower procedure-related complication rate and a shorter overall period of hospitalization. Three of the four studies reported lower 30-day mortality rates in patients treated nonoperatively, but in none of these studies did the difference achieve statistical significance, presumably because of the relatively small number of patients involved. The combined data for the four studies indicate 30-day mortality rates of 11% for patients treated with nonoperative stenting compared with 18%in patients treated surgically. One criticism of these studies is that the surgical mortality rates are much higher than reported in several recent series from North Ameri~a.~~,~~,~~ The major concern in review of these studies is the long-term results in the nonoperatively managed patients. Recurrent jaundice is seen in 17 to 38% of stented patients and seldom occurs in surgically palliated patients. Although recurrent jaundice usually can be managed by endoscopic stent change, its association with cholangitis results in significant morbidity and mortality. Whether these problems will be resolved with the use of metallic expandable stents has yet to be answered completely. The final concern that usually cannot be addressed by the nonoperative techniques is duodenal obstruction. Although not present before randomization, the incidence of late duodenal obstruction in the nonsurgical arms of these studies ranges from 9 to 14%.In the surgically managed patients, duodenal obstruction rarely occurred. The management of this late problem, often particularly difficult in the patient with advanced disease, leads many surgeons to favor surgical biliary bypass. DUODENAL OBSTRUCTION
At the time of diagnosis, 30 to 50% of patients with pancreatic cancer note symptoms of nausea and v ~ m i t i n g . Actual ~ , ~ ~ ,mechanical ~~ obstruction of the duodenum, seen on radiographic or endoscopic examination, occurs much less frequently at the time of presentation (Fig. 3).3As unresectable disease progresses, however, duodenal obstruction occurs in a significant percentage of patients. Three series have assessed the role of late duodenal obstruction. In the review by Sarr and Cameron35of more than 8000 surgically managed patients reported in the literature, 13%of patients who did not undergo gastric bypass at their initial operation required a gastrojejunostomy before death. In addition, another 20% of the remaining patients died with symptoms of duodenal obstruction. In a review of more than 950 patients in the more recent literature by Singh and Reber,39the percentage who required a gastrojejunostomy at a later date was 21%. Finally, in ~ than 1600 cases, 17% (range the review by Watanapa and W i l l i a m ~ o nof~ more 4%-44%) of patients who underwent biliary bypass alone developed duodenal obstruction at a mean of 8.6 months later and required subsequent gastric bypass.
Table 2. RESULTS OF PROSPECTIVE, RANDOMIZED TRIALS OF NONOPERATIVE VERSUS SURGICAL PALLIATION FOR MALIGNANT BlLlARY OBSTRUCTION South Africa6
N % success complications (%) 30-day mortality (%) hospital stay (days)
United Kingdom"
Stent
Surgery
Stent
Surgery
25 84 28 8 18
25 76 32 20 24*
23 82 30 9 5
25 92 56 20 13t
Denmark2 Stent
Surgery
United Kingdom12 Stent
Surgery
late complications jaundice1 cholangitis (%) gastric outlet obstruction (%) survival fwks) 'Median postprocedural hospital stay was significantly shorter in stented patients; however, when readmissionsfor late complications were considered,asignificantdifference no longer existed. tBoth initial and total hospital days were less in the stented group. $13% required two admissions for late biliary complications. §Six patients randomized to surgical arm did not undergo surgical palliation. In one patient, extensive tumor precluded palliative bypass. Five other patients underwent endoscopic stent placement. Data presented are based on randomization.
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Figure 3. Upper gastrointestinal series demonstrating duodenal obstruction by a cancer located in the head of the pancreas.
In none of these reviews did performance of a gastrojejunostomy at the original operation increase the operative mortality. However, in patients who required a second operation, mortality rates are generally higher-approaching 25%.44The authors of all of these collected reviews, therefore, favor prophylactic gastrojejunostomy in patients who undergo laparotomy for unresectable pancreatic cancer. Despite the results of these collected reviews, significant controversy continues concerning the role of prophylactic gastrojejunostomy. A number of series have shown an increase in postoperative morbidity, primarily delayed gastric , ~ ~ , ~ ~et a145also have suggested that gasemptying with this p r ~ c e d u r e . " , ' ~Weaver trojejunostomy performed in the presence of duodenal obstruction is associated ~ , ~ results have led this with a high perioperative morbidity and m ~ r t a l i t y .These group to advocate antrectomy as the procedure of choice in the setting of duodenal obstr~ction.~~ Traditionally, most surgeons have recommended performing an antecolic gastrojejunostomy to avoid placement of the gastrojejunal anastomosis in the bed of the tumor. In the Johns Hopkins series;' a retrocolic gastrojejunostomy was used in 70% of 107 patients. A strong trend toward a decreased incidence of delayed postoperative gastric emptying (6% versus 17%,P = 0.08) was seen to favor the retrocolic position versus an antecolic gastrojejunostomy. Late gastric outlet
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obstruction occurred in only 2% of patients after retrocolic anastomosis compared with 9% with the antecolic procedure ( P = 0.16). Although concern for stoma1 ulceration remains, vagotomy is not justified because it may contribute further to delayed gastric emptying. The routine use of histamine (Hz)receptor antagonists prevents this complication in most patients. Recently attempts at nonoperative palliation of duodenal obstruction have These ~ , ~techniques ~,~~ involve endoluminal placement of larger (30 been r e p ~ r t e d . ~ mm in diameter, 60-90 mm in length) metallic stents through the area of duodenal obstruction. In some patients, combined endoscopic and percutaneous access by way of an endoscopic gastrostomy is necessary. Although current experience has been limited to small series and case reports, the preliminary results are encouraging, with most patients resuming enteral nutrition until death. PAIN
Perhaps the most disturbing and incapacitating symptom of pancreatic cancer is pain. Unfortunately, for many patients, this symptom is poorly managed and remains a significant problem until death. Depending on the location of the tumor, pain can be a common symptom at presentation. In past series, up to 90% of patients reported abdominal or back pain or both at the time of presentation.16 More recently, perhaps with a greater awareness of the diagnosis, the percentage of patients with pancreatic cancer presenting with pain has decreased. Recent studies have shown that only 30 to 40% of patients with pancreatic cancer report significant pain at the time of referral, with another 30% only having minimal Yet at the time of death, most patients with unresected complaints of pain.l7fZ1 pancreatic cancer experience significant pain. The use of intraoperative chemical splanchnicectomy for unresectable pancreatic cancer was first introduced by Copping et a18 in 1978. In their subsequent report of 41 patients in 1978, 88% of patients with pain due to pancreatic cancer experienced relief of pain postoperatively.14Most of these patients underwent palliative biliary and gastrointestinal bypass at the same operation. These patients were compared with a group of historical controls in whom 21% of patients had pain control after similar palliative procedures. No complications of chemical splanchnicectomy were reported. Since that time, other anecdotal studies describing successful control with chemical splanchnicectomy have appeared. In 1993, our group at Johns Hopkins reported the first prospective, randomized, placebo-controlled study of intraoperative chemical splanchnicectomy.21All patients who underwent exploration for pancreatic cancer underwent preoperative assessment of pain and quality of life using a visual analog scale. Randomization was performed at the time of operation, when the diagnosis of unresectable pancreatic carcinoma was confirmed. Chemical splanchnicectomy was performed by injection of either 20 cc of 50% alcohol or a saline placebo on each side of the aorta at the level of the celiac axis (Fig. 4). The hospital course was monitored for postoperative complications and length of hospital stay. After hospital discharge, the patient's pain management was directed entirely by the treating physician. Follow-up pain questionnaires were completed by direct interview or by mail for all patients at 2-month intervals until their death. A total of 139 patients underwent randomization, with 2 patients excluded from chemical splanchnicectomy because of extensive tumor in the area of the celiac axis. Sixty-five of the patients received 50%alcohol injection, and 72 patients received a saline placebo. No difference was observed in hospital mortality or complications, return to oral intake, or length of hospital stay. Mean pain scores were significantly lower in the alcohol group at 2-, 4-, and 6-month follow-up and
PALLIATIVE THERAPY FOR PANCREATIC CANCER
jOO/o
209
alcohr celiac
Figure 4. Chemical splanchnicectomy is performed using a syringe and a 20- or 22-gauge spinal needle. Alcohol (20 cc of 50%) is injected on each side of the aorta at the level of the celiac axis (IVC = inferior vena cava). (From Lillemoe KD, Cameron JL, Kaufman HS, et al: Chemical splanchnicectomy in patients with unresectable pancreatic cancer: A prospective randomized trial. Ann Surg 217:447, 1993; with permission.)
at the final assessment before patient's death (Fig. 5A). In patients without preoperative pain, alcohol significantly reduced pain scores and delayed or prevented the subsequent onset of pain. In patients with significant preoperative pain, alcohol significantly reduced existing pain (Fig.5B).Furthermore, although actuarial survival was similar between the two study groups, in the subgroup of patients with significant preoperative pain, a marked improvement in survival was obtained when compared with the saline placebo (Fig. 6). These two groups were analyzed with respect to age, tumor location, tumor stage, operation performed, the use of chemotherapy and radiation therapy, baseline mood, and disability. No significant difference was apparent for any of these factors. We concluded from this study that the routine use of intraoperative chemical splanchnicectomy with
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8.0 7.0
1
1Alcohol
1
0Saline
.
N=
A
65 72 PreOp
58 58 2 mos
N=
I3
0Saline
20
17
PreOp
29 25 6 mos
.
59 62 Final
*p < 0.05
Alcohol 7.0
41 43 4 mos
+p = 0.01
19
11
2 mos
10
5
4 mos
19
12
Final
Figure 5. A, Mean pain scores measured at the preoperative, 2-, 4-, and 6-month and final assessments for all randomized patients surviving at each point. B, Mean pain scores measured at the preoperative, 2- and 4-month, and final assessments for all patients with significant preoperative pain surviving at each point. (From Lillemoe KD, Cameron JL, Kaufman HS, et al: Chemical splanchnicectomy in patients with unresectable pancreatic cancer: A prospective randomized trial. Ann Surg 217:447, 1993; with permission.)
PALLIATIVE THERAPY FOR PANCREATIC CANCER
-Alcohol pain (n
=
20)
Saline pain (n
=
14)
-----.
211
Months of Survival Figure 6. Kaplan-Meier survival curves determined from the time of hospital discharge for patients with significant preoperative pain. (From Lillemoe KD, Cameron JL, Kaufman HS, et al: Chemical splanchnicectomyin patients with unresectable pancreatic cancer:A prospective
randomized trial. Ann Surg 217:447, 1993;with permission.) alcohol should be performed in all patients who undergo laparotomy for unresectable pancreatic carcinoma. In patients who do not undergo laparotomy for pancreatic carcinoma, the appropriate use of oral agents can manage pain successfully in most patients. Patients with significant pain should receive their medication on a regular schedule and not on an as-needed basis. The use of long-acting morphine derivative compounds is best suited for such treatment. Two nonoperative treatment modalities may be used to manage intractable pain that does not respond to oral pain medication. The first major modality in pain control is percutaneous celiac nerve block performed with either fluoroscopic or CT guidance. Pain relief can be ob. ~ ~ second modality used tained in 80 to 90% of patients with this t e ~ h n i q u eThe for control of pain due to unresectable pancreatic cancer is external beam radiation therapy. Although uncontrolled, many series have shown a beneficial effect on pancreatic cancer pain in most patients. Most recently, thoroscopic splanchnicectomy and endoscopic chemical splanchnicectomy with the aid of ultrasound guidance have been introduced. However, whether these newer procedures will provide results equivalent to older techniques has yet to be determined. OVERALL RESULTS OF SURGICAL PALLIATION
Two major advantages exist for surgical palliation of pancreatic cancer. The first is the ability to combine adequate long-term palliation for all three primary symptoms of the disease. Only surgical management provides a single procedure that can relieve obstructive jaundice, treat or prevent duodenal obstruction, and reduce or prevent the significant pain associated with an unresectable tumor. The final major advantage for exploration of patients with pancreatic cancer is the potential for a curative resection. Although preoperative assessment with CT, cholangiography, visceral angiography, and laparoscopy can be valuable in the assessment of resectability, only thorough surgical exploration can rule out resect-
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ability in most patients. False acceptance of certain demise in all patients with pancreatic cancer, coupled with nonoperative palliation, denies a number of patients the opportunity for resection for cure. To justify the role of surgical palliation for pancreatic cancer, the overall results must be accomplished with acceptable morbidity and mortality. Fortunately, a number of recent series have provided excellent results with respect to perioperative morbidity and mortality, and long-term p a l l i a t i 0 n . ~ ~ ,In ~ ,the 3 ~ series , ~ ~ from Johns Hopkins of 118 patients found at surgery to have unresectable periampullary malignancy, surgical palliation was accomplished with a 2.5% hospital mortality rate.23Combined biliary bypass and gastrojejunostomy was performed in 75% of the patients. Although perioperative complications were frequent (occurring in 37% of patients), most were minor and seldom life threatening. The mean hospital stay was only 14 days, with patients returningto a regular diet at a mean of approximately 10 days. The distribution for survival for the 118 patients is shown in Figure 7, with an overall mean survival being 7.7 months. Similar results have been obtained by other groups with hospital mortality rates between 2 and 4%.10,32
LAPAROSCOPIC PALLIATION OF PANCREATIC CANCER
As with almost all areas of surgery, the use of minimally invasive surgical techniques has been applied recently to the management of pancreatic cancer. The role of diagnostic laparoscopy for the staging of pancreatic neoplasms has been well e s t a b l i ~ h e d . The ~,~~ techniques ,~~ include not only visual inspection but also ultrasonographic assessment of major visceral vesselsz6and obtaining fluid for cytologic analysis. Recently, reports have described operative techniques and reported small series of patients undergoing palliation of biliary and duodenal obstruction with laparoscopic cholecystojejunostomy and gastrojejunostomy.15~27~33
0
1-2
3-5
6-8
9-11
12-17
18-23
24+
Months Figure 7. Distribution of survival for 118 patients with unresectable periampullary carcinoma.
(From Lillemoe KD, Sauter PK, Pitt HA, et al: Current status of surgical palliation of periampullary carcinoma. Surg Gynecol Obstet, 176:1, 1993;with permission.)
PALLIATIVE THERAPY FOR PANCREATIC CANCER
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The results, although preliminary with respect to the number of patients reported, generally have shown technical success, low morbidity, and satisfactory outcomes. Whether these results can be extended to larger numbers of patients and into the hands of surgeons who are not at centers of laparoscopic surgical excellence has yet to be determined. PALLIATIVE PANCREATICODUODENECTOMY
Traditionally, pancreatic resection for cancer of the pancreas has been reserved only for patients in whom a potential for cure exists. The high morbidity and mortality associated with pancreaticoduodenectomy in the past has made this procedure inappropriate in patients when residual local disease or metastases precludes the chance for long-term cure. In the last decade, significant improvements have been noted in the perioperative morbidity and mortality for pancreaticodu~denectomy.~,'~,~~ Although the long-term results of surgical palliation are satisfactory, pancreaticoduodenectomy has potential benefits as a palliative procedure for pancreatic cancer. This role of pancreaticoduodenectomy in the palliation of pancreatic cancer was addressed recently in a retrospective comparison performed at the Johns Hopkins H o ~ p i t a lIn . ~this ~ study, 64 consecutive patients who underwent pancreaticoduodenectomy for pancreatic carcinoma with gross or microscopic evidence of adenocarcinoma at surgical resection margins were compared with 62 patients found to be unresectable at the time of laparotomy due to local invasion without evidence of metastatic disease. In the latter group, combined biliary and gastric bypass were performed for palliation in 87%of the patients. The two groups were similar with respect to age, gender, race, and presenting symptoms. The hospital mortality rate was identical for both groups at 1.6%.Fifty-eight percent of patients who underwent pancreaticoduodenectomy had an uncomplicated postoperative course compared with 68% of patients who underwent palliative bypass (not significant). The length of postoperative stay after pancreaticoduodenectomy was 18.4 days, which was significantly longer than for patients who underwent palliative bypass (15 days; P < 0.05). The overall actuarial survival (by Kaplan-Meier technique) was improved significantly in patients who underwent pancreaticoduodenectomy (P< 0.02) (Fig. 8).Postoperative chemotherapy and radiation therapy improved survival in both groups. Although this nonrandomized retrospective study can be criticized because of the questionable true compatibility of the two groups, the study does suggest that paIIiative pancreaticoduodenectorny, if performed with acceptably low perioperative morbidity and mortality, may offer some advantages to patients with seemingly unresectable disease. The incidence of rehospitalization after pancreaticoduodenectomy was 11%, whereas 20% of nonresected patients were readmitted to the hospital after their initial hospital discharge. Three of the nonresected patients required reoperation, whereas none of the patients who underwent pancreaticoduodenectomy required a subsequent operation. These differences were not significant as a comparison of quality of life. CONCLUSIONS
The decision to perform nonoperative versus surgical palliation for unresectable pancreatic cancer is influenced by a number of factors. In most cases, patient symptoms most clearly dictate the management. In patients with symptoms of
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-Palliative Pancreaticoduodenectomy
:.:!\..
- - - .- .
Palliative Bypass
... ....
p<0.02
Months Figure 8. Actuarial survival curves (Kaplan-Meier)for patients undergoing palliative pancreaticoduodenectomy (n = 64) and palliative bypass (n = 62). (From Lillemoe KD, Cameron JL, Yeo CJ, et al: Pancreaticoduodenectomy:Does it have a role in the palliation of pancreatic cancer? Ann Surg 223:718, 1996; with permission.)
duodenal obstruction at the time of presentation, surgery is the only option. In patients with obstructive jaundice alone, the options for management must be weighed against factors such as overall health status, projected survival, and procedure-related morbidity and mortality. A prospective multicenter trial recently analyzed factors that influence perioperative morbidity and mortality after pan. ~ analysis demonstrated that preoperative diabetes, low Kancreatic ~ u r g e r yThis ofsky's index, and liver metastases are significant risk factors in predicting perioperative morbidity and mortality in patients who undergo palliative procedures for pancreatic cancer. Another analysis that focused on tumor characteristicssuggests that for patients with stage I and stage I1 disease (i.e., with no evidence of systemic metastases), survival and the potential for late duodenal obstruction favor surgical management for these patient^.'^ In summary, although patient management must be individualized, most patients with pancreatic cancer who are in good medical health and have no evidence of systemicdisease are most appropriately managed with surgical palliation. This option affords them the best chance of avoidance of the late complications of recurrent jaundice, duodenal obstruction, and disabling pain. Surgical palliation generally can be completed with an acceptable perioperative morbidity and mortality as well as a hospital stay in the range of 2 weeks. Finally, only with surgical exploration can the opportunity for resection for cure be evaluated completely.
PALLIATIVE THERAPY FOR PANCREATIC CANCER
215
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Address reprint requests to Keith D. Lillemoe, MD The Johns Hopkins Hospital 600 North Wolfe Street Blalock 679 Baltimore, MD 21287-4679