Regional Pancreatectomy: En Bloc Pancreatic, Portal Vein and Lymph Node Resection JOSEPH G. FORTNER, M.D., DONG K. KIM, M.D., ANTONIO CUBILLA, M.D., ALAN TURNBULL, M.D., LYLE D. PAHNKE, M.D., MAURICE E. SHILS, M.D.
From the Gastric and Mixed Tumor Service, Department of Surgery, Surgical Pathology Service, Department of Pathology, Department of Anesthesiology, Clinical Physiology and Renal Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York
Eighteen patients are reported who have had a regional pancreatectomy. The pancreatic segment of portal vein was excised with the en bloc total pancreatectomy and regional lymph node dissection in all 18. Venous repair was by end-toend anastomosis without a graft. Five of the 18 also had various arterial resections and reconstructions. Sixteen of the 18 had been explored and deemed nonresectable elsewhere. This operation has doubled the resectability rate in this institution. The 30-day operative mortality rate was 16.6%. Acturarial survival is 62% at one year compared with 36% one year survival rate for patients undergoing pancreaticoduodenectomy for less advanced cancer in previous years. A more valid comparison would be between those who had a palliative procedure since most patients in the present series were initially considered unresectable. One year survival for these patients was 22%. The quality of life was good for most patients.
carried out, but the portal vein is not taken (i.e., for a small lesion in the distal body or tail of the pancreas). The operation (Type I) was performed for the first time on February 1, 1972, and preliminary reports made in 1973 and 1974.10,11 This communication describes our more recent experiences with these operations which have been applied systematically during the past two years to 18 patients. Sixteen had been declared nonresectable elsewhere. Using this procedure has increased the resectability rate for cancer of the pancreas at this institution from 18% to 40%. One year survival rates have been increased to 62% from previous years results of 36% for patients undergoing pancreaticoduodenectomy or 22% for comparable patients who had bypass operations.
N EW WAYS TO DEAL with vascular barriers to resecting cancer of the pancreas and a basis for
improved survival rates are provided by the operation, regional pancreatectomy. This therapeutic approach is suited also to many deeply invasive cancers of the ampulla, as well as for cancers of the periampullary region and duodenum. The operation is an en bloc resection of the pancreas with adjacent soft tissue and transverse mesocolon, regional lymph nodes and pertinent vascular structures. The three main types are based upon the vascular procedures employed. Resection of the portal vein en bloc with the pancreas is done in the Type I operation. (The defect is repaired without a graft by anastomosis of the superior mesenteric vein to residual portal vein.) Additional removal of the hepatic and/or superior mesenteric arteries for more extensive cancers is a Type II operation. A Type 0 procedure is one in which the extensive en bloc resection of a Type I operation is
Materials and Methods Fifty-two patients with cancers of the pancreas, ampulla, duodenum or distal common bile duct were treated by the authors from April 1974 to April 1976. Twenty-one (40%o) had a curative type of resection with 18 or 34.6% of the 52 having regional pancreatectomies. Two patients had a standard pancreaticoduodenectomy: one for a cancer arising in the ampulla and the other in the distal common bile duct. One total pancreatectomy for cancer of the head of the pancreas was performed in a poor risk patient. Palliative surgery was done for 31 individuals whose disease had extended beyond regional confines. Only patients with regional pancreatectomy are considered in this report. This group is composed of 8 women ranging in age
Submitted for publication: September 2, 1976. Reprint Requests Joseph G. Fortner, MD, Chief, Gastric and Mixed Tumor Service, Department of Surgery, Memorial SloanKettering Cancer Center, 1275 York Avenue, New York, New York 10021.
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from 43 to 64 years and 10 men who were 40 to 66 years old. Eleven had pancreatic duct adenocarcinoma. Seven individuals had extensive cancers of other types: adenocarcinoma originating in the duodenum-3; ampullary adenocarcinoma- 1; terminal bile duct adenosquamous carcinoma- 1; adenocarcinoma of indeterminate origin- 1; islet cell carcinoma involving head and body of the pancreas- 1. Twelve patients were referred with a positive pancreatic cancer biopsy obtained at a prior laparotomy. A positive biopsy was obtained by transduodenal needle biopsy in five other individuals at time of regional pancreatectomy. Resection was based on clinical judgement in one patient after multiple negative biopsies. Baseline xylose absorption tests2 were done on nine patients. Supplemental studies were repeated after one to 6 months. Clinical Status Extensive reaction to prior surgery, severe pancreatitis and large tumors were present in nearly all patients. Eight patients were particularly difficult: (1) tumor grossly encased the common hepatic artery and gastroduodenal artery; (2) tumor extended in the porta hepatis nearly to the liver, vascular anomalies were present and the patient was severely jaundiced; (3) a previous distal pancreatectomy with Roux-en-Y pancreaticojejunostomy for presumed recurrent acute pancreatitis led to the discovery of cancer which had been only partially removed; (4) prior choledochostomy, sphincterotomy, biopsy, T-tube insertion and a postoperative wound infection; (5) cholecystocolonic fistula with gallstones impacted in the fistula; (6) wound infection with patient in such poor general condition that intravenous alimentation was necessary for five to 6 weeks preoperatively; (7) severe jaundice and oral herpes; (8) non-function of right kidney with narrowing of the inferior vena cava by invasive tumor and compression of the portal venous system as revealed by angiography.
Surgical Procedures Type I A total pancreatectomy is done with removal of the pancreatic segment of portal vein, transverse mesocolon with middle colic vessels, surrounding soft tissues and regional lymph nodes. A subtotal gastrectomy, duodenectomy, splenectomy, and removal of gallbladder and common bile duct are included. The portal vein, hepatic artery, celiac axis and superior mesenteric artery are skeletonized. A retroperitoneal node dissection from the diaphragm above, to the origin
43
of the inferior mesenteric artery below, is carried out. Laterally, Gerotas fascia is incised and reflected medially from the renal hilum with removal of soft tissue and lymph nodes lateral and medial to the aorta and vena cava. The defect in the portal venous system is repaired by pushing the base of the small bowel mesentery cephalad and doing an end-to-end anastomosis of superior mesenteric vein to the portal vein. A vein graft is unnecessary and has not been used. An end-to-side choledochojejunostomy and gastrojejunostomy complete the procedure. Type II The celiac axis, hepatic and/or superior mesenteric arteries are removed as an addition to the Type I procedure. There are three subtypes. Type Ila-A segment of superior mesenteric artery is removed.Reconstruction is by end-to-end anastomosis of the artery, an endto-side anastomosis to the aorta, or by replacement of the vessel with a saphenous vein graft or arterial prosthesis. Type Ilb-The celiac axis and/or hepatic artery are removed. The defect is repaired by end-toend anastomosis of hepatic artery to the base of the splenic, common hepatic arteries or the celiac axis. Alternately, it can be repaired with a saphenous vein graft or arterial prosthesis connecting the common hepatic artery to the aorta. Type Ilc-Both celiac axis and superior mesenteric artery are removed and reconstructed separately or with a bifurcated arterial
prosthesis. Type 0 A Type I procedure is done except for removal of the portal vein segment. Results The mean operating time was 10 hours ranging from 8 to 12 hours. Intraoperative blood replacement was 5 to 27 units with a mean of 10 units (5000 cc). Postoperative hospitalization averaged 53 days, ranging from 38 to 89 days. The intensive care unit stay averaged 10 days, but ranged from 5 to 38 days. Thirteen patients had the Type I and five a Type II procedure (Table 1). Resection of an area of inferior vena cava about 6 x 3 cm in conjunction with a right nephrectomy was done in addition to the Type I procedure in one patient. The defect was repaired with the resected segment of portal vein which was made into a patch graft. This segment was well away from tumor and could be used safely. A second modification of the Type I procedure was necessary in another patient. Here, the right hepatic artery arose from the superior mesenteric artery, crossed posterior to the pancreas, but could be
44
FORTNER AND OTHERS
TABLE 1. Vascular Resection and Reconstruction Type I
portal vein resection with end-to-end anastomosis segmental resection of inferior vena cava and reconstruction with patch graft of portal vein resection of celiac axis and left hepatic artery without reconstruction Type
II
portal vein resection with end-to-end anastomosis
mid-portion superior mesenteric artery resection with end-to-end anastomosis proximal superior mesenteric artery resected with end-to-side anastomosis to aorta resection of right hepatic artery with anastomosis to base of splenic artery resection of common hepatic artery with anastomosis of right hepatic artery to splenic artery and left hepatic artery to celiac axis
dissected from the tumor. The celiac axis and left hepatic artery were involved in the tumor and were resected with the mass. Vascular reconstruction was not done. No untoward effects were noted in either patient. Three of the Type II pancreatectomies were subgroup a. In two instances, the mid portion of superior mesenteric artery was resected with the pancreas and an end-to-end anastomosis of the shortened superior mesenteric artery carried out. In the third patient, an end-to-side anastomosis of the distal half of superior mesenteric artery to the aorta was done. There were no vascular complications. Vascular procedures on the superior mesenteric artery were preceded by cannulation of a small jejunal branch for perfusion and chilling of the temporarily devascularized bowel. Chilled Ringer's lactate was used as a perfusate with the effluent collected from the transected end of superior mesenteric vein. Two patients had a subgroup b procedure. In one, the right hepatic artery arose from the superior mesenteric artery and crossed through the tumor. It was resected and the hepatic artery was anastomosed to the base of the splenic artery at the celiac axis. There were no apparent complications. A second patient had resection of the common hepatic artery and anastomosis of the right hepatic artery to the base of the splenic artery and the left hepatic artery was anastomosed to the celiac axis at the common hepatic artery takeoff. The vessels were severely arteriosclerotic resulting in thrombosis of the right hepatic artery and liver infarction and death ofthe patient about 72 hours postoperatively.
Ann. Surg.
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July 1977
Portal venous occlusion times were recorded for 15 of the patients. It varied from 8 to 35 minutes with an average of 14.5 minutes. Upper and lower lines of transection of the vein were invariably beyond gross tumor and pancreatic margins. The length in the surgical specimen was measured in only 6 instances, where it varied from two to 6.5 cm with an average of 4.2 cm. Neither heparinization nor temporary occlusion of the superior mesenteric artery were used during the time of portal vein occlusion. A subtotal gastric resection was done in 14 patients. The left gastric artery and venous drainage from the lesser curvature and superior surface of the stomach were preserved. In two early patients, extensive dissection of the venous drainage of the stomach caused massive hemorrhage and congestion of the gastric remnant which was controlled by ligation of the left gastric artery. In Types IIb and IIc regional pancreatectomies, a total or near total gastrectomy is necessary. Sacrifice of the left gastric artery with the accompanying extensive dissection in these operations leads to dependence on the phrenic vessels. This has proved to be hazardous. In the present series, a total gastrectomy was necessary in three patients and one had all but 10% of the stomach removed. Preservation of the vascular arcade of the transverse mesocolon permitted safe ligation of the middle colic vessels and inclusion of the transverse mesocolon with the en bloc resection. Blood supply of the transverse colon was from the ileocolic and inferior mesenteric vessels. Inadvertent ligation of the inferior mesenteric artery in two early cases and tumor encroachment in 6 was the basis for removal of the transverse colon in 8 patients. In two of these, the ascending and descending colons and proximal jejunum were removed; in one, the proximal jejunum was included and in another, the ascending colon and right kidney were removed. Two of the patients who had resection of the transverse colon were among the three who had a total gastrectomy also. Reconstruction was invariably by an end-toend anastomosis of the remaining intestinal tract. Biliary tract reconstruction was by an end-to-side anastomosis in 13 patients and by end-to-end in five. Neither a T-tube, other stent, nor external drainage were used. Anastomosis was by a single layer, interrupted 4-0 silk suture of the inverting type. Pathology Duct Adenocarcinoma of the Pancreas The distribution of these tumors within the pancreas is listed in Table 2. Grossly they were firm, white-gray and sclerotic with poorly circumscribed outlines measuring from 2.5 to 9 cm. in the largest dimension
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(average 5.1 cm) Microscopically, the eleven cases showed a well- to moderately well-differentiated duct adenocarcinoma, with prominent desmoplastic reaction. Obstructive pancreatitis in the form of acinar atrophy, fibrosis and chronic inflammation was noted in all cases.. Perineural invasion was found in 9 cases. In the 11 patients, one or more of the following adjacent structures were directly invaded microscopically: portal vein-6; duodenum-8; stomach-2; and ampulla of Vater- 1. in situ or intraductal carcinoma was noted in addition to the invasive neoplasm in three cases (27%). In one, multifocal in situ cancer was in the area surrounding the invasive neoplasm. Multicentric, atypical hyperplasia below the histologic level of carcinomain situ was noted in another patient with an invasive adenocarcinoma in the head. These changes were present in the main and intermediate pancreatic ducts throughout the head, body and tail. In another case, following distal pancreatectomy for carcinoma of the tail at another hospital, regional pancreatectomy revealed multiple foci of intraductal carcinoma in the stump of residual body of the pancreas. In the one patient with involvement of the head, body and tail, a portion of pancreatic body contained no cancer between the tumor mass in the tail and the other in the body and head. The average number of lymph nodes per specimen was 73. Metastases to regional lymph nodes were present in nine ofthe 11 cases. The most common anatomic groups19 involved were the superior group in 6 patients; inferior group in six patients; posterior group in four patients. The number of positive lymph nodes per patient varied from one to 18 with an average of five. Tumors Other Than Duct Adenocarcinoma of Pancreas
Duodenal adenocarcinomas (three cases) were firm, constricting, ulcerating and infiltrating in two instances. In the third, the tumor was soft, polypoid and gelatinous. The ampullary adenocarcinoma was a small, indurated, white-grey tumor of the ampulla of Vater which infiltrated the papillary portion of duodenum and underlying pancreatic tissue. The bile duct carcinoma was mostly an intraluminal, firm, white-gray tumor involving the common bile duct 1 cm. above the ampulla. The duct was destroyed in one area and pancreatic tissue was also involved. The islet cell carcinoma was a solid, rubbery tan to white-yellow tumor involving the head of pancreas and infiltrating the duodenal wall and portal vein. The portal vein was occluded by a tumor thrombosis 4 cm long and 1.5 cm wide. The adenocarcinoma of indeterminate origin was a large (9 cm) fungating and ulcerating neoplasm involving the entire thickness of duodenal wall, pan-
45 TABLE 2. Pathological Findings
Duct Adenocarcinoma of Pancreas (11 cases)
Anatomical Site head head-body body-tail head-body-tail Total
No. of Cases
Average Size (cm)
7 2 I 1
4.2 6.2 unknown 9 5.1
11
Average No. of Positive Lymph Nodes 6.1 I
0 3 4.8
Tumor Other Than Duct Adenocarcinoma of Pancreas (7 cases)
duodenal adenocarcinoma ampullary adenocarcinoma bile duct adenosquamous adenocarcinoma of indeterminate origin islet cell carcinoma Total
3 1 1
11 1.5 2.5
0 2
l 1 7
9 6 7.4
1.2
I
creas, bile duct, right renal vein, renal pelvis and inferior vena cava. The average size of the lesions are listed in Table 2. Histologically, all tumors except for the islet cell carcinoma were adenocarcinoma with mucin production. The bile duct lesion had a squamous carcinoma component (adenosquamous carcinoma). The average number of lymph nodes in these resected specimens was 70. Regional lymph node metastasis was noted in four of the seven cases. The number of lymph nodes containing metastatic carcinoma in the four cases was 1, 2, 3, and 3, respectively. The patient with only one positive lymph node had an islet cell carcinoma. Metabolic Consequences Fluid Requirements Sequestration of plasma into the gastrointestinal tract was evident intraoperatively by edema of the bowel wall. Plasma loss from the raw surfaces of dissected areas and leakage from transected lymphatics were also present. Large volumes of colloid replacement were given to compensate for this loss. In 13 Type I regional pancreatectomies an average of 3.3 liters (2.0 to 4.8 liters) were given during the operation. The five Type II operations required somewhat more being 4.4 liters on the average (range 3.2 to 6.1 liters). Maintenance of an adequate urine output was assured by sufficient crystalloid infusion. Colloid requirements continued to be large for the first three to four postoperative days. Most patients required as much as 1.5 liters per day during this period. Four or about 20% were given more than 1.5 liters per day. Type II regionally pancreatectomized patients did
FORTNER AND OTHERS
46
/
30-
20.Z
10
10
1 *
3
. July
1977
fat emulsion (intralipid) has improved the management of these patients in the postoperative period. After stabilization of diet and increasing physical activity, NPH was substituted for regular insulin on a daily basis, the amount initially being approximately one-half to two-thirds the previous average daily regular insulin requirement. Insulin requirements gradually decreased with time, averaging 17 units NPH daily (8-30 units range) after four months. Increases in insulin requirements were usually due to occult infection or dietary changes. This proved to be the first manifestation of recurrent cancer in two patients several months after discharge from the hospital.
70
mgm%
Ann. Surg.
5
7
9
11
Time in months indicates colectomy
FIG. 1. Xylose absorption test 2 hour blood level peak.
not require significantly more colloid maintenance than the Type I patients postoperatively.
Insulin Management
Four to 6 units of regular insulin were given subcutaneously every 6 hours to cover 5% glucose infusions in the early postoperative period. This dose was regulated according to blood glucose levels and correlated with urinary glucose spillage. Patients were found to be extremely sensitive to insulin. Every effort was made to maintain serum blood sugar levels of 180-280 mgo with mild glycosuria during the first postoperative weeks. Ketoacidosis was avoided, but hypoglycemic episodes occurred in 50% of patients during hospitalization. Total parenteral nutrition provided caloric support until oral intake was adequate. In recent cases, patients maintained on total parenteral nutritional after leaving the intensive care unit have been maintained by combination of intravenous insulin (starting with 1 unit regular insulin for every 100 glucose calories and modifying as indicated) plus q6h coverage for urine glucose above 1 +. Recent use of intravenous
Nutritional Appetite was characteristically poor in the initial stages of recovery necessitating parenteral nutrition for three to five weeks after surgery. Xylose absorption was found to be impaired during the first postoperative month (Fig. 1). Initially, the degree of impairment varied greatly between patients but all improved to normal at approximately the same rate. The time required for this was related directly to the severity of initial impairment and the amount of gastrointestinal tract resected. Frequent, thin, mucoid stools were usually noted within 48 hours after surgery. This subsided after several days until oral feedings began. Bowel movements then were usually watery, loose and frequent, with stools occurring 7 to 8 times per day; they were different in fluid loss, and consistency and appearance from that expected from pancreatic insufficiency alone. Treatment of the loss of endogenous pancreatic enzymes was with Cotazymg or viokase, three to four capsules with each meal. The evident hypermotility was slowed with opiates or lomotil. As absorption improved, most patients acclimated to two or three formed stools per day. Two patients have had prolonged diarrheal states. One patient with marked malTABLE 3. Postoperative Complications 1. Hemorrhage 2. Fistula a. gastrojejunal b. colon 3. Severe Diarrhea and Malabsorption 4. Pleural Effusion a. cancer cells identified b. serous 5. Mental Depression and Withdrawal 6. Infections a. wound infection b. pneumonia c. sepsis with control d. sepsis with multiple organ failure 2
3 6 2 4 4
6 3 3 2 8 6 8 2
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REGIONAL PANCREATECTOMY
47
Regional pancreatectomy 4/74-4/76: 15 pts.
.Whipple resection 1959-1969: 17 pts.
100r
Bypass procedure 1959-1969: 77 pts.
80~
L
FIG. 2. Probability of survival from cancer death (vertical axis represents percentage).
6 alive more than 12 months (3 NED. 3 AWD) 2 withdrawn alive (2 NED)
7 l
'- -- t
_______________l_________
60
L.L
40 I
L.._
_
v
disease
2 other cause 1 unknown cause
;-______-L5 alive more than 12 months 112 died: 9 of disease 3 other cause
t
17 alive more than 12 months, 60 died
20 I I
V
l4 of
2
fi
4
,
I
6
8 10 Months after surgery
absorption associated with jejunal and colon resection required total parenteral nutrition (TPN) at home20 until his absorption improved. Protein and fat absorptions were not studied but appeared to be imparied for three to four months when the patients' nutritional status generally improved. Postoperative weight loss has stabilized at an average of 23% less than the preoperative weight (range 10- 37%). Iron, calcium and phosphorus deficiencies have not been observed with careful attention to diet. Magnesium deficiency has occurred in the several patients with marked malabsorption following cessation of total parenteral nutrition. Bowel fistulas occuring in 6 patients closed spontaneously with TPN in five cases. One fistula was closed surgically. Morbidity and Mortality Table 3 lists the postoperative complications. Those of most serious import, such as gastrointestinal fistula occurred in the earlier patients of this series. There were three postoperative deaths within 30 days of operation giving a mortality rate of 16.6%. One death occurred on the fourteenth postoperative day from multiple complications which were sequelae of necrosis of the common bile duct. At necropsy this patient also had thrombosis of the portal vein although angiography on the sixth postoperative day showed a normal portal venous system. Sepsis and three operative attempts to control hemobilia may have been contributing factors. A second patient died of a myocardial infarction 72 hours after surgery without undue operative stress or
12
hypotensive episodes. The preoperative electrocardiohad been normal. The third death was due to hepatic artery thrombosis and liver infarction after hepatic artery resection as indicated previously. There were two deaths from complications more than 30 days after surgery. One was from massive pulmonary embolism occurring five weeks after surgery in a patient nearly recovered after a stormy postoperative course. The second death occurred at another hospital about two and a half months after surgery, of an unknown cause. gram
Survival Rates and Performance Status Eight of the 15 individuals (53%) who survived the operation are living for periods ranging from four to 17 months. Six are living more than one year after regional pancreatectomy. Actuarial survival by Kaplan-Meier14 estimate is 62% at one year (Fig. 2), compared with a 36% one year survival rate for 17 patients undergoing pancreaticoduodenectomy for less advanced cancer at Memorial Sloan-Kettering Cancer Center from 19591969.12 A more valid comparison would be between those who had a palliative procedure since most of the patients in the present series were initially considered unresectable. There were 77 patients in this group and 22% were alive at one year. Although the subgroup is small, consideration of patients with pancreatic duct adenocarcinoma separately revealed that four of 9 patients (44%) who survived the operation are alive at 4 to 15.5 months. Three of the four are without evidence of recurrent cancer. Two of the
Ann. Surg.
FORTNER AND OTHERS
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July 1977
TABLE 4. Potential Contributing Factors for Recurrent Cancer within 6 Months
Pancreatic Duct Cancer
Lymph Node Metastases
Microscopically Positive Margins of Resection
Apparent Rapid Growth Rate (Death from Cancer)
directly invaded
cancer encircling common hepatic artery cut through
recurrence 4.5 months after
common bile duct and inferior mesenteric vein,
recurrence 4 months after
Case 3
extensive with infiltration of duodenum, wall of inferior mesenteric vein; splenic vein thrombosis infiltration of duodenal wall, ampulla and common bile duct; bile contained isolated cancer cells extensive
multiple positive
common bile duct and jejunum
recurrence 4 months after resection
Case 4
extensive
2 positive intra pancreatic
common bile duct
recurrence 4 months after resection
Case 5
head and body pancreas, extension into duodenal tissue
serosal implant base middle colic vessels
none
2nd cancer- bronchogenic primary; died-8 months cerebral metastases
rt. kidney nonfunctioning with vena cava and soft tissue infiltration
multiple
recurrence 7 months after resection
2.5 cm mass in head, adenosquamous; + biopsy through common bile duct-spillage of bile possibly containing cancer cells
two
inferior vena cava (soft tissue extension permitted only narrow resection everywhere) none
Case 1
Case 2
Other Cancer Case 6
Case 7
Primary Cancer
21 of 81 lymph nodes were positive
operation
operation
peritoneal surface
four patients with advanced cancers other than pancreatic duct who are presently alive are without evidence of recurrent cancer. Results were evaluated further by applying the Karnofsky Performance Scale15 to these patients who are presently alive. It was found that four are in the 90%o, one is in the 80% and three are in the 70%o group. Thus, five are able to carry on normal activity and need no special care. Three are unable to work, but live at home and care for themselves. Recurrent Disease Patients identified as developing recurrent disease within 6 months of regional pancreatectomy were reviewed. Table 4 shows factors which seem likely to have contributed to failure of treatment. Microscopic cancer at or near the line of transection, particularly the common bile duct, appears to be a prominent factor. Discussion Historically, creation of the operation pancreaticoduodenectomy5'23 (Whipple procedure) was a therapeutic milestone. Surgeons were then able to remove cancers of the ampulla, periampullary region, duodenum and pancreas and to cope with the inherent
recurrence 6 months after
resection
complex anatomical and metabolic problems. The operation has given good cure rates for certain of these cancers, most notably those arising in the ampulla. 1,3,16,17,22 Longevity and comfort has been achieved for patients with adenocarcinomas of the pancreas, but five year cure rates for this cancer have been low. Extension of the operation to that of a total pancreatectomy was an important advance.4'7'8'13'18 The therapeutic implication of the multifocal nature of pancreatic cancer was recognized. Margins of resection of the tumor were increased and more lymph nodes were removed. Improved five year survival rates are a reflection of its merits. These operations, pancreaticoduodenectomy (or distal pancreatectomy) and total pancreatectomy, however, have certain limitations. The resectability rate is low for cancers of the pancreas, varying from 5% to 18% of patients. Proximity of tumor to the portal vein precludes resection in nearly one-third of these nonresectable patients.16 Even in resectable cases, dissection of pancreatic branches to the portal vein necessarily violates the protective barrier of the pancreatic pseudocapsule and may lead to inadvertent spillage of tumor. Furthermore, consideration of the lymphatic drainage of the pancreas suggests that lymph node
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REGIONAL PANCREATECTOMY
dissections accompanying pancreaticoduodenectomy or total pancreatectomy are incomplete, being an incidental part of the operation. Particularly significant is the high local recurrence rate indicating need for a greater margin of soft tissue resection around the pancreas.21 Patients in the present series presented formidable surgical problems. Sixteen of the 18 had been previously explored and declared non-resectable. The associated pancreatitis, reaction to previous surgery and large tumors contributed to the difficult technical problems encountered. Despite this, the operations were carried out with morbidity and mortality rates which compare favorably with those for pancreaticoduodenectomy and total pancreatectomy. Causes for some of the postoperative deaths can be avoided in future cases. Necrosis of the extrahepatic bile ducts can be prevented by transecting the common hepatic duct near its bifurcation. This avoids the possibility of decreased vascularity in a common bile duct which may have been compromised during the hilar dissection. A stress cardiogram preoperatively will diminish the possibility of undetected obliterative coronary artery disease being present. The risk of thrombosis of hepatic or superior mesenteric arteries can be minimized by avoiding anastomosis of small vessels which are severely damaged by arteriosclerosis. The potential of death from massive pulmonary embolism can be minimized in future patients by pneumatic calf compression. Preliminary biliary tract decompression before regional pancreatectomy is essential because of the increased morbidity and mortality rates experienced by jaundiced patients who had this procedure. Most patients developing recurrence did so due to an inadequate margin of resection usually at the common bile duct. This can be avoided by high transection of the common hepatic duct. If this is impossible, the patient should be declared non-resectable. Patients who have smaller lesions with less reactive inflammatory changes and pancreatitis should have a low morbidity and mortality rate, particularly where preliminary decompression of the obstructed biliary tree is carried out. Improved survival rates, both early and late, should result. The operation of regional pancreatectomy appears to be sound in that it adheres to basic cancer surgical principles of wide excision of the cancer en bloc with lymph nodes draining the anatomical region of the cancer. Cubilla9 has recently compared the number of lymph nodes removed by a pancreaticoduodenectomy, total pancreatectomy and regional pancreatectomy. These averaged, respectively, 28, 48, and 73. The average number of positive nodes was three, four, and 6, respectively. Regional pancreatectomy combines
49
this more effective removal of regional lymph nodes with recognition of the multicentric origin or in situ nature of nearly one-fifth of pancreatic cancers by including total pancreatectomy. Particularly important in this operation is the ability to carry out major vascular resections and reconstructions as part of routine upper abdominal visceral resections. It has been demonstrated that the pancreatic segment of portal vein can be resected as a routine measure en bloc with the pancreas and the defect repaired with a simple end-to end anastomosis of superior mesenteric and portal veins without need for a graft. Arterial resections and reconstructions can be carried out utilizing grafts or arterial branches for reconstructions. A portion of the right hepatic artery, for example, can be anastomosed to the base of the splenic artery. These capabilities increase the resectability rate as well as increasing the number of options available to the surgeon for dealing with cancer in patients who frequently have vascular anomalies which potentiate an already complicated clinical setting. Experience with these patients suggests that this procedure is most appropriate for less advanced lesions ordinarily treated by a standard pancreaticoduodenectomy. Past results with small lesions treated by pancreaticoduodenectomy are almost as dismal as those for larger lesions. It is with the less formidable lesions that the greatest likelihood exists of obtaining a cure from this operation. Metabolic alterations of the operation are major. Initially, large quantities of colloid are needed to replace losses occurring from the large deperitonealized surface, lymphatic dissection and transected small bowel mesentery. Characteristically, these losses diminish sharply after three days. Another finding, that of insulin sensitivity of the totally pancreatectomized patient has been well documented previously.6 The third major metabolic consequence is decreased intestinal absorption secondary to the loss of pancreatic exocrine function and loss of upper gastrointestinal tract. Severance of lymphatic drainage and small bowel denervation undoubtedly contribute. This problem is presently under investigation. Gastrointestinal fistula is a complication which was distressingly common in the earlier cases. It appears to have been from loss of adequate venous drainage from the gastrointestinal tract. Preservation of venous drainage on the lesser curvature of the stomach above the level of the left gastric artery as well as superiorly on the diaphragmatic aspect has obviated gastrojejunal fistulizations. Any questionally compromised area of venous drainage from the colon is treated by resection of the colonic segment. This is usually at the hepatic flexure when it occurs. Otherwise careful preservation
50
FORTNER AND OTHERS
of the vascular arcade from the ileocolic to inferior mesenteric vessels has greatly diminished the frequency of this complication. Total parenteral nutrition in the postoperative period using intravenous fat and covering glucose by intravenous insulin is important. Peripheral parenteral nutrition using fat and amino acids with 10% glucose to supplement oral intake in the early recovery period is helpful. Cancer cells were identified in the pleural fluid of three patients following resection. Although the cytologic diagnosis appears correct, cancer has not recurred in these patients. The finding is of concern for it could represent leakage of cells from the transected ends of lymphatics into the peritoneal cavity. A communication might exist between the abdominal and thoracic cavities after an extensive dissection. Preoperative radiation and/or chemotherapy might be used as an effective deterrent to this complication. Resectability rates for cancer of the pancreas have been doubled while maintaining mortality rates which are comparable to those of prior years. Therapeutic effectiveness can be measured only in a preliminary fashion at this time. One year survival on an actuarial basis is 62% for the present series. This compares favorably with previous results from this institution where- only 36% of patients who underwent pancreaticoduodenectomy for pancreatic cancer lived one year after resection; only 22% subjected to a bypass procedure lived this long. Particularly important is the good quality of life of surviving patients. References 1. Aston, S. J., and Longmire, W. P., Jr.: Pancreaticoduodenal Resection. Twenty Years' Experience. Arch. Surg., 106:813,
1973. 2. Benson, J. A., Jr., Culver, P. J., Ragland, S., et al.: The D-Xylose Absorption Test in Malabsorption Syndrome. N. Engl. J. Med., 256:335, 1957. 3. Bowden, L., and Pack, G. T.: Cancer of the Head of the Pancreas. A Collective Review of the Experience of the Gastric Service of Memorial Cancer Center 1926-1958. Separata de G.E.N., 23:339, 1969.
Ann. Surg. * July 1977
4. Brooks, J. R., and Culebras, J. M.: Cancer of the Pancreas: Palliative Operation, Whipple Procedure or Total Pancreatectomy. Am. J. Surg. 131:516, 1976. 5. Brunschwig, A.: Resection of the Head of Pancreas and Duodenum for Carcinoma-Pancreatoduodenectomy. Surg. Gynecol. Obstet., 65:681, 1937. 6. Burton, T. Y., Kearns, T. P., and Rynearson, E. H.: Diabetic Retinopathy Following Total Pancreatectomy. Mayo Clin. Proc., 32:735, 1957. 7. Castellanos, J., Manifacio, G., Lillehei, R. C., et al.: Total Pancreatectomy for Ductal Carcinoma of the Head of the Pancreas-Current Status. Am. J. Surg., 131:595, 1976. 8. Collins, J. J. Jr., Craighead, J. E., and Brooks, J. R.: Rationale for Total Pancreatectomy for Carcinoma of the Pancreatic Head. N. Engl. J. Med., 274:599, 1966. 9. Cubilla, A.: Unpublished observations. 10. Fortner, J. G.: Regional Resection of Cancer of the Pancreas. A New Surgical Approach. Surgery, 73:307, 1973. 11. Fortner, J. G.: Recent Advances in Pancreatic Cancer. Surg. Clinics North Am., 54:859, 1974. 12. Fortner, J. G.: Unpublished data. 13. Hicks, R. E. and Brooks, J. R.: Total Pancreatectomy for Ductal Carcinoma. Surg. Gynecol. Obstet., 133:16, 1971. 14. Kaplan, E. L., and Meier, P.: Nonparametric Estimation from Incomplete Observations. J. Am. Stat. Assoc., 53:457, 1958. 15. Karnofsky, D. A., and Burchenal, J. H.: Clinical Evaluation of Chemotherapeutic Agents in Cancer, In Evaluation of Chemotherapeutic Agents, MacLeod, C. N., Editor, New York, Columbia University Press, 1949, pp. 191-205. 16. Monge, J. J., Judd, E. S., and Gage, R. P.: Radical Pancreatoduodenectomy. A 22-Year Experience With the Complications, Mortality Rate and Survival Rate. Ann. Surg., 160:711, 1964. 17. Morris, P. J., and Nardi, G. L.: Pancreatioduodenal Cancer. Experience from 1951 to 1960 With a Look Ahead and Behind. Arch. Surg., 92:834, 1966. 18. ReMine, W. H., Priestley, J. T., Judd, E. S., et al.: Total Pancreatectomy. Ann. Surg., 172:595, 1970. 19. Rouviere, H.: Anatomy of the Human Lymphatic System, Ann Arbor, Michigan, Edward Brothers, 1938, p. 203. 20. Shils, M. E.: A Program For Total Parenteral Nutrition at Home. Am. J. Clin. Nutr., 28:1429, 1975 21. Tepper, T., Nardi, G., and Suit, H.: Carcinoma of the Pancreas: Review of MGH Experience From 1963 to 1973. Analysis of Surgical Failure and Implications for Radiation Therapy. Cancer, 37:1519, 1976. 22. Warren, K. W., Braasch, J. W., and Thum, C. W.: Diagnosis and Surgical Treatment of Carcinoma of the Pancreas. Curr. Prob. Surg., 2:1, 1968. 23. Whipple, A. O., Parsons, W. W., and Mullins, C. R.: Treatment of Carcinoma of the Ampulla of Vater. Ann. Surg., 102:763, 1935.
From the Gastric and Mixed Tumor Service, Department of Surgery, Surgical Pathology Service, Department of Pathology, Department of Anesthesiology, Clinical Physiology and Renal Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York
Eighteen patients are reported who have had a regional pancreatectomy. The pancreatic segment of portal vein was excised with the en bloc total pancreatectomy and regional lymph node dissection in all 18. Venous repair was by end-toend anastomosis without a graft. Five of the 18 also had various arterial resections and reconstructions. Sixteen of the 18 had been explored and deemed nonresectable elsewhere. This operation has doubled the resectability rate in this institution. The 30-day operative mortality rate was 16.6%. Acturarial survival is 62% at one year compared with 36% one year survival rate for patients undergoing pancreaticoduodenectomy for less advanced cancer in previous years. A more valid comparison would be between those who had a palliative procedure since most patients in the present series were initially considered unresectable. One year survival for these patients was 22%. The quality of life was good for most patients.
carried out, but the portal vein is not taken (i.e., for a small lesion in the distal body or tail of the pancreas). The operation (Type I) was performed for the first time on February 1, 1972, and preliminary reports made in 1973 and 1974.10,11 This communication describes our more recent experiences with these operations which have been applied systematically during the past two years to 18 patients. Sixteen had been declared nonresectable elsewhere. Using this procedure has increased the resectability rate for cancer of the pancreas at this institution from 18% to 40%. One year survival rates have been increased to 62% from previous years results of 36% for patients undergoing pancreaticoduodenectomy or 22% for comparable patients who had bypass operations.
N EW WAYS TO DEAL with vascular barriers to resecting cancer of the pancreas and a basis for
improved survival rates are provided by the operation, regional pancreatectomy. This therapeutic approach is suited also to many deeply invasive cancers of the ampulla, as well as for cancers of the periampullary region and duodenum. The operation is an en bloc resection of the pancreas with adjacent soft tissue and transverse mesocolon, regional lymph nodes and pertinent vascular structures. The three main types are based upon the vascular procedures employed. Resection of the portal vein en bloc with the pancreas is done in the Type I operation. (The defect is repaired without a graft by anastomosis of the superior mesenteric vein to residual portal vein.) Additional removal of the hepatic and/or superior mesenteric arteries for more extensive cancers is a Type II operation. A Type 0 procedure is one in which the extensive en bloc resection of a Type I operation is
Materials and Methods Fifty-two patients with cancers of the pancreas, ampulla, duodenum or distal common bile duct were treated by the authors from April 1974 to April 1976. Twenty-one (40%o) had a curative type of resection with 18 or 34.6% of the 52 having regional pancreatectomies. Two patients had a standard pancreaticoduodenectomy: one for a cancer arising in the ampulla and the other in the distal common bile duct. One total pancreatectomy for cancer of the head of the pancreas was performed in a poor risk patient. Palliative surgery was done for 31 individuals whose disease had extended beyond regional confines. Only patients with regional pancreatectomy are considered in this report. This group is composed of 8 women ranging in age
Submitted for publication: September 2, 1976. Reprint Requests Joseph G. Fortner, MD, Chief, Gastric and Mixed Tumor Service, Department of Surgery, Memorial SloanKettering Cancer Center, 1275 York Avenue, New York, New York 10021.
42
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REGIONAL PANCREATECTOMY
from 43 to 64 years and 10 men who were 40 to 66 years old. Eleven had pancreatic duct adenocarcinoma. Seven individuals had extensive cancers of other types: adenocarcinoma originating in the duodenum-3; ampullary adenocarcinoma- 1; terminal bile duct adenosquamous carcinoma- 1; adenocarcinoma of indeterminate origin- 1; islet cell carcinoma involving head and body of the pancreas- 1. Twelve patients were referred with a positive pancreatic cancer biopsy obtained at a prior laparotomy. A positive biopsy was obtained by transduodenal needle biopsy in five other individuals at time of regional pancreatectomy. Resection was based on clinical judgement in one patient after multiple negative biopsies. Baseline xylose absorption tests2 were done on nine patients. Supplemental studies were repeated after one to 6 months. Clinical Status Extensive reaction to prior surgery, severe pancreatitis and large tumors were present in nearly all patients. Eight patients were particularly difficult: (1) tumor grossly encased the common hepatic artery and gastroduodenal artery; (2) tumor extended in the porta hepatis nearly to the liver, vascular anomalies were present and the patient was severely jaundiced; (3) a previous distal pancreatectomy with Roux-en-Y pancreaticojejunostomy for presumed recurrent acute pancreatitis led to the discovery of cancer which had been only partially removed; (4) prior choledochostomy, sphincterotomy, biopsy, T-tube insertion and a postoperative wound infection; (5) cholecystocolonic fistula with gallstones impacted in the fistula; (6) wound infection with patient in such poor general condition that intravenous alimentation was necessary for five to 6 weeks preoperatively; (7) severe jaundice and oral herpes; (8) non-function of right kidney with narrowing of the inferior vena cava by invasive tumor and compression of the portal venous system as revealed by angiography.
Surgical Procedures Type I A total pancreatectomy is done with removal of the pancreatic segment of portal vein, transverse mesocolon with middle colic vessels, surrounding soft tissues and regional lymph nodes. A subtotal gastrectomy, duodenectomy, splenectomy, and removal of gallbladder and common bile duct are included. The portal vein, hepatic artery, celiac axis and superior mesenteric artery are skeletonized. A retroperitoneal node dissection from the diaphragm above, to the origin
43
of the inferior mesenteric artery below, is carried out. Laterally, Gerotas fascia is incised and reflected medially from the renal hilum with removal of soft tissue and lymph nodes lateral and medial to the aorta and vena cava. The defect in the portal venous system is repaired by pushing the base of the small bowel mesentery cephalad and doing an end-to-end anastomosis of superior mesenteric vein to the portal vein. A vein graft is unnecessary and has not been used. An end-to-side choledochojejunostomy and gastrojejunostomy complete the procedure. Type II The celiac axis, hepatic and/or superior mesenteric arteries are removed as an addition to the Type I procedure. There are three subtypes. Type Ila-A segment of superior mesenteric artery is removed.Reconstruction is by end-to-end anastomosis of the artery, an endto-side anastomosis to the aorta, or by replacement of the vessel with a saphenous vein graft or arterial prosthesis. Type Ilb-The celiac axis and/or hepatic artery are removed. The defect is repaired by end-toend anastomosis of hepatic artery to the base of the splenic, common hepatic arteries or the celiac axis. Alternately, it can be repaired with a saphenous vein graft or arterial prosthesis connecting the common hepatic artery to the aorta. Type Ilc-Both celiac axis and superior mesenteric artery are removed and reconstructed separately or with a bifurcated arterial
prosthesis. Type 0 A Type I procedure is done except for removal of the portal vein segment. Results The mean operating time was 10 hours ranging from 8 to 12 hours. Intraoperative blood replacement was 5 to 27 units with a mean of 10 units (5000 cc). Postoperative hospitalization averaged 53 days, ranging from 38 to 89 days. The intensive care unit stay averaged 10 days, but ranged from 5 to 38 days. Thirteen patients had the Type I and five a Type II procedure (Table 1). Resection of an area of inferior vena cava about 6 x 3 cm in conjunction with a right nephrectomy was done in addition to the Type I procedure in one patient. The defect was repaired with the resected segment of portal vein which was made into a patch graft. This segment was well away from tumor and could be used safely. A second modification of the Type I procedure was necessary in another patient. Here, the right hepatic artery arose from the superior mesenteric artery, crossed posterior to the pancreas, but could be
44
FORTNER AND OTHERS
TABLE 1. Vascular Resection and Reconstruction Type I
portal vein resection with end-to-end anastomosis segmental resection of inferior vena cava and reconstruction with patch graft of portal vein resection of celiac axis and left hepatic artery without reconstruction Type
II
portal vein resection with end-to-end anastomosis
mid-portion superior mesenteric artery resection with end-to-end anastomosis proximal superior mesenteric artery resected with end-to-side anastomosis to aorta resection of right hepatic artery with anastomosis to base of splenic artery resection of common hepatic artery with anastomosis of right hepatic artery to splenic artery and left hepatic artery to celiac axis
dissected from the tumor. The celiac axis and left hepatic artery were involved in the tumor and were resected with the mass. Vascular reconstruction was not done. No untoward effects were noted in either patient. Three of the Type II pancreatectomies were subgroup a. In two instances, the mid portion of superior mesenteric artery was resected with the pancreas and an end-to-end anastomosis of the shortened superior mesenteric artery carried out. In the third patient, an end-to-side anastomosis of the distal half of superior mesenteric artery to the aorta was done. There were no vascular complications. Vascular procedures on the superior mesenteric artery were preceded by cannulation of a small jejunal branch for perfusion and chilling of the temporarily devascularized bowel. Chilled Ringer's lactate was used as a perfusate with the effluent collected from the transected end of superior mesenteric vein. Two patients had a subgroup b procedure. In one, the right hepatic artery arose from the superior mesenteric artery and crossed through the tumor. It was resected and the hepatic artery was anastomosed to the base of the splenic artery at the celiac axis. There were no apparent complications. A second patient had resection of the common hepatic artery and anastomosis of the right hepatic artery to the base of the splenic artery and the left hepatic artery was anastomosed to the celiac axis at the common hepatic artery takeoff. The vessels were severely arteriosclerotic resulting in thrombosis of the right hepatic artery and liver infarction and death ofthe patient about 72 hours postoperatively.
Ann. Surg.
9
July 1977
Portal venous occlusion times were recorded for 15 of the patients. It varied from 8 to 35 minutes with an average of 14.5 minutes. Upper and lower lines of transection of the vein were invariably beyond gross tumor and pancreatic margins. The length in the surgical specimen was measured in only 6 instances, where it varied from two to 6.5 cm with an average of 4.2 cm. Neither heparinization nor temporary occlusion of the superior mesenteric artery were used during the time of portal vein occlusion. A subtotal gastric resection was done in 14 patients. The left gastric artery and venous drainage from the lesser curvature and superior surface of the stomach were preserved. In two early patients, extensive dissection of the venous drainage of the stomach caused massive hemorrhage and congestion of the gastric remnant which was controlled by ligation of the left gastric artery. In Types IIb and IIc regional pancreatectomies, a total or near total gastrectomy is necessary. Sacrifice of the left gastric artery with the accompanying extensive dissection in these operations leads to dependence on the phrenic vessels. This has proved to be hazardous. In the present series, a total gastrectomy was necessary in three patients and one had all but 10% of the stomach removed. Preservation of the vascular arcade of the transverse mesocolon permitted safe ligation of the middle colic vessels and inclusion of the transverse mesocolon with the en bloc resection. Blood supply of the transverse colon was from the ileocolic and inferior mesenteric vessels. Inadvertent ligation of the inferior mesenteric artery in two early cases and tumor encroachment in 6 was the basis for removal of the transverse colon in 8 patients. In two of these, the ascending and descending colons and proximal jejunum were removed; in one, the proximal jejunum was included and in another, the ascending colon and right kidney were removed. Two of the patients who had resection of the transverse colon were among the three who had a total gastrectomy also. Reconstruction was invariably by an end-toend anastomosis of the remaining intestinal tract. Biliary tract reconstruction was by an end-to-side anastomosis in 13 patients and by end-to-end in five. Neither a T-tube, other stent, nor external drainage were used. Anastomosis was by a single layer, interrupted 4-0 silk suture of the inverting type. Pathology Duct Adenocarcinoma of the Pancreas The distribution of these tumors within the pancreas is listed in Table 2. Grossly they were firm, white-gray and sclerotic with poorly circumscribed outlines measuring from 2.5 to 9 cm. in the largest dimension
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(average 5.1 cm) Microscopically, the eleven cases showed a well- to moderately well-differentiated duct adenocarcinoma, with prominent desmoplastic reaction. Obstructive pancreatitis in the form of acinar atrophy, fibrosis and chronic inflammation was noted in all cases.. Perineural invasion was found in 9 cases. In the 11 patients, one or more of the following adjacent structures were directly invaded microscopically: portal vein-6; duodenum-8; stomach-2; and ampulla of Vater- 1. in situ or intraductal carcinoma was noted in addition to the invasive neoplasm in three cases (27%). In one, multifocal in situ cancer was in the area surrounding the invasive neoplasm. Multicentric, atypical hyperplasia below the histologic level of carcinomain situ was noted in another patient with an invasive adenocarcinoma in the head. These changes were present in the main and intermediate pancreatic ducts throughout the head, body and tail. In another case, following distal pancreatectomy for carcinoma of the tail at another hospital, regional pancreatectomy revealed multiple foci of intraductal carcinoma in the stump of residual body of the pancreas. In the one patient with involvement of the head, body and tail, a portion of pancreatic body contained no cancer between the tumor mass in the tail and the other in the body and head. The average number of lymph nodes per specimen was 73. Metastases to regional lymph nodes were present in nine ofthe 11 cases. The most common anatomic groups19 involved were the superior group in 6 patients; inferior group in six patients; posterior group in four patients. The number of positive lymph nodes per patient varied from one to 18 with an average of five. Tumors Other Than Duct Adenocarcinoma of Pancreas
Duodenal adenocarcinomas (three cases) were firm, constricting, ulcerating and infiltrating in two instances. In the third, the tumor was soft, polypoid and gelatinous. The ampullary adenocarcinoma was a small, indurated, white-grey tumor of the ampulla of Vater which infiltrated the papillary portion of duodenum and underlying pancreatic tissue. The bile duct carcinoma was mostly an intraluminal, firm, white-gray tumor involving the common bile duct 1 cm. above the ampulla. The duct was destroyed in one area and pancreatic tissue was also involved. The islet cell carcinoma was a solid, rubbery tan to white-yellow tumor involving the head of pancreas and infiltrating the duodenal wall and portal vein. The portal vein was occluded by a tumor thrombosis 4 cm long and 1.5 cm wide. The adenocarcinoma of indeterminate origin was a large (9 cm) fungating and ulcerating neoplasm involving the entire thickness of duodenal wall, pan-
45 TABLE 2. Pathological Findings
Duct Adenocarcinoma of Pancreas (11 cases)
Anatomical Site head head-body body-tail head-body-tail Total
No. of Cases
Average Size (cm)
7 2 I 1
4.2 6.2 unknown 9 5.1
11
Average No. of Positive Lymph Nodes 6.1 I
0 3 4.8
Tumor Other Than Duct Adenocarcinoma of Pancreas (7 cases)
duodenal adenocarcinoma ampullary adenocarcinoma bile duct adenosquamous adenocarcinoma of indeterminate origin islet cell carcinoma Total
3 1 1
11 1.5 2.5
0 2
l 1 7
9 6 7.4
1.2
I
creas, bile duct, right renal vein, renal pelvis and inferior vena cava. The average size of the lesions are listed in Table 2. Histologically, all tumors except for the islet cell carcinoma were adenocarcinoma with mucin production. The bile duct lesion had a squamous carcinoma component (adenosquamous carcinoma). The average number of lymph nodes in these resected specimens was 70. Regional lymph node metastasis was noted in four of the seven cases. The number of lymph nodes containing metastatic carcinoma in the four cases was 1, 2, 3, and 3, respectively. The patient with only one positive lymph node had an islet cell carcinoma. Metabolic Consequences Fluid Requirements Sequestration of plasma into the gastrointestinal tract was evident intraoperatively by edema of the bowel wall. Plasma loss from the raw surfaces of dissected areas and leakage from transected lymphatics were also present. Large volumes of colloid replacement were given to compensate for this loss. In 13 Type I regional pancreatectomies an average of 3.3 liters (2.0 to 4.8 liters) were given during the operation. The five Type II operations required somewhat more being 4.4 liters on the average (range 3.2 to 6.1 liters). Maintenance of an adequate urine output was assured by sufficient crystalloid infusion. Colloid requirements continued to be large for the first three to four postoperative days. Most patients required as much as 1.5 liters per day during this period. Four or about 20% were given more than 1.5 liters per day. Type II regionally pancreatectomized patients did
FORTNER AND OTHERS
46
/
30-
20.Z
10
10
1 *
3
. July
1977
fat emulsion (intralipid) has improved the management of these patients in the postoperative period. After stabilization of diet and increasing physical activity, NPH was substituted for regular insulin on a daily basis, the amount initially being approximately one-half to two-thirds the previous average daily regular insulin requirement. Insulin requirements gradually decreased with time, averaging 17 units NPH daily (8-30 units range) after four months. Increases in insulin requirements were usually due to occult infection or dietary changes. This proved to be the first manifestation of recurrent cancer in two patients several months after discharge from the hospital.
70
mgm%
Ann. Surg.
5
7
9
11
Time in months indicates colectomy
FIG. 1. Xylose absorption test 2 hour blood level peak.
not require significantly more colloid maintenance than the Type I patients postoperatively.
Insulin Management
Four to 6 units of regular insulin were given subcutaneously every 6 hours to cover 5% glucose infusions in the early postoperative period. This dose was regulated according to blood glucose levels and correlated with urinary glucose spillage. Patients were found to be extremely sensitive to insulin. Every effort was made to maintain serum blood sugar levels of 180-280 mgo with mild glycosuria during the first postoperative weeks. Ketoacidosis was avoided, but hypoglycemic episodes occurred in 50% of patients during hospitalization. Total parenteral nutrition provided caloric support until oral intake was adequate. In recent cases, patients maintained on total parenteral nutritional after leaving the intensive care unit have been maintained by combination of intravenous insulin (starting with 1 unit regular insulin for every 100 glucose calories and modifying as indicated) plus q6h coverage for urine glucose above 1 +. Recent use of intravenous
Nutritional Appetite was characteristically poor in the initial stages of recovery necessitating parenteral nutrition for three to five weeks after surgery. Xylose absorption was found to be impaired during the first postoperative month (Fig. 1). Initially, the degree of impairment varied greatly between patients but all improved to normal at approximately the same rate. The time required for this was related directly to the severity of initial impairment and the amount of gastrointestinal tract resected. Frequent, thin, mucoid stools were usually noted within 48 hours after surgery. This subsided after several days until oral feedings began. Bowel movements then were usually watery, loose and frequent, with stools occurring 7 to 8 times per day; they were different in fluid loss, and consistency and appearance from that expected from pancreatic insufficiency alone. Treatment of the loss of endogenous pancreatic enzymes was with Cotazymg or viokase, three to four capsules with each meal. The evident hypermotility was slowed with opiates or lomotil. As absorption improved, most patients acclimated to two or three formed stools per day. Two patients have had prolonged diarrheal states. One patient with marked malTABLE 3. Postoperative Complications 1. Hemorrhage 2. Fistula a. gastrojejunal b. colon 3. Severe Diarrhea and Malabsorption 4. Pleural Effusion a. cancer cells identified b. serous 5. Mental Depression and Withdrawal 6. Infections a. wound infection b. pneumonia c. sepsis with control d. sepsis with multiple organ failure 2
3 6 2 4 4
6 3 3 2 8 6 8 2
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REGIONAL PANCREATECTOMY
47
Regional pancreatectomy 4/74-4/76: 15 pts.
.Whipple resection 1959-1969: 17 pts.
100r
Bypass procedure 1959-1969: 77 pts.
80~
L
FIG. 2. Probability of survival from cancer death (vertical axis represents percentage).
6 alive more than 12 months (3 NED. 3 AWD) 2 withdrawn alive (2 NED)
7 l
'- -- t
_______________l_________
60
L.L
40 I
L.._
_
v
disease
2 other cause 1 unknown cause
;-______-L5 alive more than 12 months 112 died: 9 of disease 3 other cause
t
17 alive more than 12 months, 60 died
20 I I
V
l4 of
2
fi
4
,
I
6
8 10 Months after surgery
absorption associated with jejunal and colon resection required total parenteral nutrition (TPN) at home20 until his absorption improved. Protein and fat absorptions were not studied but appeared to be imparied for three to four months when the patients' nutritional status generally improved. Postoperative weight loss has stabilized at an average of 23% less than the preoperative weight (range 10- 37%). Iron, calcium and phosphorus deficiencies have not been observed with careful attention to diet. Magnesium deficiency has occurred in the several patients with marked malabsorption following cessation of total parenteral nutrition. Bowel fistulas occuring in 6 patients closed spontaneously with TPN in five cases. One fistula was closed surgically. Morbidity and Mortality Table 3 lists the postoperative complications. Those of most serious import, such as gastrointestinal fistula occurred in the earlier patients of this series. There were three postoperative deaths within 30 days of operation giving a mortality rate of 16.6%. One death occurred on the fourteenth postoperative day from multiple complications which were sequelae of necrosis of the common bile duct. At necropsy this patient also had thrombosis of the portal vein although angiography on the sixth postoperative day showed a normal portal venous system. Sepsis and three operative attempts to control hemobilia may have been contributing factors. A second patient died of a myocardial infarction 72 hours after surgery without undue operative stress or
12
hypotensive episodes. The preoperative electrocardiohad been normal. The third death was due to hepatic artery thrombosis and liver infarction after hepatic artery resection as indicated previously. There were two deaths from complications more than 30 days after surgery. One was from massive pulmonary embolism occurring five weeks after surgery in a patient nearly recovered after a stormy postoperative course. The second death occurred at another hospital about two and a half months after surgery, of an unknown cause. gram
Survival Rates and Performance Status Eight of the 15 individuals (53%) who survived the operation are living for periods ranging from four to 17 months. Six are living more than one year after regional pancreatectomy. Actuarial survival by Kaplan-Meier14 estimate is 62% at one year (Fig. 2), compared with a 36% one year survival rate for 17 patients undergoing pancreaticoduodenectomy for less advanced cancer at Memorial Sloan-Kettering Cancer Center from 19591969.12 A more valid comparison would be between those who had a palliative procedure since most of the patients in the present series were initially considered unresectable. There were 77 patients in this group and 22% were alive at one year. Although the subgroup is small, consideration of patients with pancreatic duct adenocarcinoma separately revealed that four of 9 patients (44%) who survived the operation are alive at 4 to 15.5 months. Three of the four are without evidence of recurrent cancer. Two of the
Ann. Surg.
FORTNER AND OTHERS
9
July 1977
TABLE 4. Potential Contributing Factors for Recurrent Cancer within 6 Months
Pancreatic Duct Cancer
Lymph Node Metastases
Microscopically Positive Margins of Resection
Apparent Rapid Growth Rate (Death from Cancer)
directly invaded
cancer encircling common hepatic artery cut through
recurrence 4.5 months after
common bile duct and inferior mesenteric vein,
recurrence 4 months after
Case 3
extensive with infiltration of duodenum, wall of inferior mesenteric vein; splenic vein thrombosis infiltration of duodenal wall, ampulla and common bile duct; bile contained isolated cancer cells extensive
multiple positive
common bile duct and jejunum
recurrence 4 months after resection
Case 4
extensive
2 positive intra pancreatic
common bile duct
recurrence 4 months after resection
Case 5
head and body pancreas, extension into duodenal tissue
serosal implant base middle colic vessels
none
2nd cancer- bronchogenic primary; died-8 months cerebral metastases
rt. kidney nonfunctioning with vena cava and soft tissue infiltration
multiple
recurrence 7 months after resection
2.5 cm mass in head, adenosquamous; + biopsy through common bile duct-spillage of bile possibly containing cancer cells
two
inferior vena cava (soft tissue extension permitted only narrow resection everywhere) none
Case 1
Case 2
Other Cancer Case 6
Case 7
Primary Cancer
21 of 81 lymph nodes were positive
operation
operation
peritoneal surface
four patients with advanced cancers other than pancreatic duct who are presently alive are without evidence of recurrent cancer. Results were evaluated further by applying the Karnofsky Performance Scale15 to these patients who are presently alive. It was found that four are in the 90%o, one is in the 80% and three are in the 70%o group. Thus, five are able to carry on normal activity and need no special care. Three are unable to work, but live at home and care for themselves. Recurrent Disease Patients identified as developing recurrent disease within 6 months of regional pancreatectomy were reviewed. Table 4 shows factors which seem likely to have contributed to failure of treatment. Microscopic cancer at or near the line of transection, particularly the common bile duct, appears to be a prominent factor. Discussion Historically, creation of the operation pancreaticoduodenectomy5'23 (Whipple procedure) was a therapeutic milestone. Surgeons were then able to remove cancers of the ampulla, periampullary region, duodenum and pancreas and to cope with the inherent
recurrence 6 months after
resection
complex anatomical and metabolic problems. The operation has given good cure rates for certain of these cancers, most notably those arising in the ampulla. 1,3,16,17,22 Longevity and comfort has been achieved for patients with adenocarcinomas of the pancreas, but five year cure rates for this cancer have been low. Extension of the operation to that of a total pancreatectomy was an important advance.4'7'8'13'18 The therapeutic implication of the multifocal nature of pancreatic cancer was recognized. Margins of resection of the tumor were increased and more lymph nodes were removed. Improved five year survival rates are a reflection of its merits. These operations, pancreaticoduodenectomy (or distal pancreatectomy) and total pancreatectomy, however, have certain limitations. The resectability rate is low for cancers of the pancreas, varying from 5% to 18% of patients. Proximity of tumor to the portal vein precludes resection in nearly one-third of these nonresectable patients.16 Even in resectable cases, dissection of pancreatic branches to the portal vein necessarily violates the protective barrier of the pancreatic pseudocapsule and may lead to inadvertent spillage of tumor. Furthermore, consideration of the lymphatic drainage of the pancreas suggests that lymph node
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REGIONAL PANCREATECTOMY
dissections accompanying pancreaticoduodenectomy or total pancreatectomy are incomplete, being an incidental part of the operation. Particularly significant is the high local recurrence rate indicating need for a greater margin of soft tissue resection around the pancreas.21 Patients in the present series presented formidable surgical problems. Sixteen of the 18 had been previously explored and declared non-resectable. The associated pancreatitis, reaction to previous surgery and large tumors contributed to the difficult technical problems encountered. Despite this, the operations were carried out with morbidity and mortality rates which compare favorably with those for pancreaticoduodenectomy and total pancreatectomy. Causes for some of the postoperative deaths can be avoided in future cases. Necrosis of the extrahepatic bile ducts can be prevented by transecting the common hepatic duct near its bifurcation. This avoids the possibility of decreased vascularity in a common bile duct which may have been compromised during the hilar dissection. A stress cardiogram preoperatively will diminish the possibility of undetected obliterative coronary artery disease being present. The risk of thrombosis of hepatic or superior mesenteric arteries can be minimized by avoiding anastomosis of small vessels which are severely damaged by arteriosclerosis. The potential of death from massive pulmonary embolism can be minimized in future patients by pneumatic calf compression. Preliminary biliary tract decompression before regional pancreatectomy is essential because of the increased morbidity and mortality rates experienced by jaundiced patients who had this procedure. Most patients developing recurrence did so due to an inadequate margin of resection usually at the common bile duct. This can be avoided by high transection of the common hepatic duct. If this is impossible, the patient should be declared non-resectable. Patients who have smaller lesions with less reactive inflammatory changes and pancreatitis should have a low morbidity and mortality rate, particularly where preliminary decompression of the obstructed biliary tree is carried out. Improved survival rates, both early and late, should result. The operation of regional pancreatectomy appears to be sound in that it adheres to basic cancer surgical principles of wide excision of the cancer en bloc with lymph nodes draining the anatomical region of the cancer. Cubilla9 has recently compared the number of lymph nodes removed by a pancreaticoduodenectomy, total pancreatectomy and regional pancreatectomy. These averaged, respectively, 28, 48, and 73. The average number of positive nodes was three, four, and 6, respectively. Regional pancreatectomy combines
49
this more effective removal of regional lymph nodes with recognition of the multicentric origin or in situ nature of nearly one-fifth of pancreatic cancers by including total pancreatectomy. Particularly important in this operation is the ability to carry out major vascular resections and reconstructions as part of routine upper abdominal visceral resections. It has been demonstrated that the pancreatic segment of portal vein can be resected as a routine measure en bloc with the pancreas and the defect repaired with a simple end-to end anastomosis of superior mesenteric and portal veins without need for a graft. Arterial resections and reconstructions can be carried out utilizing grafts or arterial branches for reconstructions. A portion of the right hepatic artery, for example, can be anastomosed to the base of the splenic artery. These capabilities increase the resectability rate as well as increasing the number of options available to the surgeon for dealing with cancer in patients who frequently have vascular anomalies which potentiate an already complicated clinical setting. Experience with these patients suggests that this procedure is most appropriate for less advanced lesions ordinarily treated by a standard pancreaticoduodenectomy. Past results with small lesions treated by pancreaticoduodenectomy are almost as dismal as those for larger lesions. It is with the less formidable lesions that the greatest likelihood exists of obtaining a cure from this operation. Metabolic alterations of the operation are major. Initially, large quantities of colloid are needed to replace losses occurring from the large deperitonealized surface, lymphatic dissection and transected small bowel mesentery. Characteristically, these losses diminish sharply after three days. Another finding, that of insulin sensitivity of the totally pancreatectomized patient has been well documented previously.6 The third major metabolic consequence is decreased intestinal absorption secondary to the loss of pancreatic exocrine function and loss of upper gastrointestinal tract. Severance of lymphatic drainage and small bowel denervation undoubtedly contribute. This problem is presently under investigation. Gastrointestinal fistula is a complication which was distressingly common in the earlier cases. It appears to have been from loss of adequate venous drainage from the gastrointestinal tract. Preservation of venous drainage on the lesser curvature of the stomach above the level of the left gastric artery as well as superiorly on the diaphragmatic aspect has obviated gastrojejunal fistulizations. Any questionally compromised area of venous drainage from the colon is treated by resection of the colonic segment. This is usually at the hepatic flexure when it occurs. Otherwise careful preservation
50
FORTNER AND OTHERS
of the vascular arcade from the ileocolic to inferior mesenteric vessels has greatly diminished the frequency of this complication. Total parenteral nutrition in the postoperative period using intravenous fat and covering glucose by intravenous insulin is important. Peripheral parenteral nutrition using fat and amino acids with 10% glucose to supplement oral intake in the early recovery period is helpful. Cancer cells were identified in the pleural fluid of three patients following resection. Although the cytologic diagnosis appears correct, cancer has not recurred in these patients. The finding is of concern for it could represent leakage of cells from the transected ends of lymphatics into the peritoneal cavity. A communication might exist between the abdominal and thoracic cavities after an extensive dissection. Preoperative radiation and/or chemotherapy might be used as an effective deterrent to this complication. Resectability rates for cancer of the pancreas have been doubled while maintaining mortality rates which are comparable to those of prior years. Therapeutic effectiveness can be measured only in a preliminary fashion at this time. One year survival on an actuarial basis is 62% for the present series. This compares favorably with previous results from this institution where- only 36% of patients who underwent pancreaticoduodenectomy for pancreatic cancer lived one year after resection; only 22% subjected to a bypass procedure lived this long. Particularly important is the good quality of life of surviving patients. References 1. Aston, S. J., and Longmire, W. P., Jr.: Pancreaticoduodenal Resection. Twenty Years' Experience. Arch. Surg., 106:813,
1973. 2. Benson, J. A., Jr., Culver, P. J., Ragland, S., et al.: The D-Xylose Absorption Test in Malabsorption Syndrome. N. Engl. J. Med., 256:335, 1957. 3. Bowden, L., and Pack, G. T.: Cancer of the Head of the Pancreas. A Collective Review of the Experience of the Gastric Service of Memorial Cancer Center 1926-1958. Separata de G.E.N., 23:339, 1969.
Ann. Surg. * July 1977
4. Brooks, J. R., and Culebras, J. M.: Cancer of the Pancreas: Palliative Operation, Whipple Procedure or Total Pancreatectomy. Am. J. Surg. 131:516, 1976. 5. Brunschwig, A.: Resection of the Head of Pancreas and Duodenum for Carcinoma-Pancreatoduodenectomy. Surg. Gynecol. Obstet., 65:681, 1937. 6. Burton, T. Y., Kearns, T. P., and Rynearson, E. H.: Diabetic Retinopathy Following Total Pancreatectomy. Mayo Clin. Proc., 32:735, 1957. 7. Castellanos, J., Manifacio, G., Lillehei, R. C., et al.: Total Pancreatectomy for Ductal Carcinoma of the Head of the Pancreas-Current Status. Am. J. Surg., 131:595, 1976. 8. Collins, J. J. Jr., Craighead, J. E., and Brooks, J. R.: Rationale for Total Pancreatectomy for Carcinoma of the Pancreatic Head. N. Engl. J. Med., 274:599, 1966. 9. Cubilla, A.: Unpublished observations. 10. Fortner, J. G.: Regional Resection of Cancer of the Pancreas. A New Surgical Approach. Surgery, 73:307, 1973. 11. Fortner, J. G.: Recent Advances in Pancreatic Cancer. Surg. Clinics North Am., 54:859, 1974. 12. Fortner, J. G.: Unpublished data. 13. Hicks, R. E. and Brooks, J. R.: Total Pancreatectomy for Ductal Carcinoma. Surg. Gynecol. Obstet., 133:16, 1971. 14. Kaplan, E. L., and Meier, P.: Nonparametric Estimation from Incomplete Observations. J. Am. Stat. Assoc., 53:457, 1958. 15. Karnofsky, D. A., and Burchenal, J. H.: Clinical Evaluation of Chemotherapeutic Agents in Cancer, In Evaluation of Chemotherapeutic Agents, MacLeod, C. N., Editor, New York, Columbia University Press, 1949, pp. 191-205. 16. Monge, J. J., Judd, E. S., and Gage, R. P.: Radical Pancreatoduodenectomy. A 22-Year Experience With the Complications, Mortality Rate and Survival Rate. Ann. Surg., 160:711, 1964. 17. Morris, P. J., and Nardi, G. L.: Pancreatioduodenal Cancer. Experience from 1951 to 1960 With a Look Ahead and Behind. Arch. Surg., 92:834, 1966. 18. ReMine, W. H., Priestley, J. T., Judd, E. S., et al.: Total Pancreatectomy. Ann. Surg., 172:595, 1970. 19. Rouviere, H.: Anatomy of the Human Lymphatic System, Ann Arbor, Michigan, Edward Brothers, 1938, p. 203. 20. Shils, M. E.: A Program For Total Parenteral Nutrition at Home. Am. J. Clin. Nutr., 28:1429, 1975 21. Tepper, T., Nardi, G., and Suit, H.: Carcinoma of the Pancreas: Review of MGH Experience From 1963 to 1973. Analysis of Surgical Failure and Implications for Radiation Therapy. Cancer, 37:1519, 1976. 22. Warren, K. W., Braasch, J. W., and Thum, C. W.: Diagnosis and Surgical Treatment of Carcinoma of the Pancreas. Curr. Prob. Surg., 2:1, 1968. 23. Whipple, A. O., Parsons, W. W., and Mullins, C. R.: Treatment of Carcinoma of the Ampulla of Vater. Ann. Surg., 102:763, 1935.
