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1 Surgical Principles for Pancreatic Cancer: Regional Total and Subtotal Pancreatectomy JOSEPH G. FORTNER. MD During the period , regional pancreatectomy has been performed in 40 patients: 36 had periampullary or pancreatic cancer, and 4 patients had benign disease. The 30-day postoperative mortality rate is 15% (6140) overall, being 7% for the regional total pancreatectomy Type 1, 29% for Type 11, and 50% for regional subtotal Type I. Of the 30 patients with cancer who survived the operation, 33% are currently alive and 27% have died of other causes with no evidence of recurrent disease. An analysis of treatment failures in the remaining 12 patients (40%) who died of disease is presented. Cancer 47: , HE UTTER 1NEFFECTlVENESS Of most SUrgiCal pro- T cedures, radiation therapy, and chemotherapy for cancer of the pancreas has led understandably to widespread defeatism in caring for such patients. A similar condition exists also for invasive ampullary, periampullary, and duodenal cancers. As a result, a palliative biliary enteric bypass without resection is considered a preferable form of therapy for these cancer patients by many surgeons. This philosophy would indeed appear correct if the surgical treatment being evaluated is a pancreaticoduodenectomy. The poor results obtained by surgeons worldwide attest to its ineffectiveness even for small cancers. For example, eight patients with a small primary pancreatic cancer and without overt metastases were treated with a bypass procedure for a variety of reasons at Memorial Sloan-Kettering Cancer Center. Their mean survival was 16.8 months. This is essentially the same as the mean survival time of 16.2 months for 18 patients treated by pancreaticoduodenectomy. The mean survival of 77 other patients with more advanced adenocarcinomas of the pancreas treated by palliative bypass was 8.4 months. These survival rates clearly relate to the stage of disease. Prolonged survival after palliative bypass as reported by Crile' is undoubtedly due in nearly all instances to faulty pathologic interpretations of limited biopsy material. Presented at the International Meeting on Pancreatic Cancer, Louisiana State University School of Medicine, New Orleans, Louisiana, March 10-11, From the Gastric and Mixed Tumor Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York. Address for reprints: Joseph G. Fortner, MD, Memorial Sloan- Kettering Cancer Center, 1275 York Avenue, New York NY Accepted for publication August 26, Total pancreatectomy appears to give improved cure ~-ates.~.'l-'~ The procedure has been carried out largely as a way to avoid pancreatic fistula after pancreaticoduodenectomy. Despite this, it achieves a somewhat greater margin around the tumor and removes multifocal disease. Proximity or attachment to the portal vein precludes resection. The emphasis in this operation appears misplaced, concentrating more upon removing more pancreas rather than achieving greater adherence to basic surgical oncologic principles. En bloc resection of the primary cancer with a wide tissue margin and with its regional lymphatic drainage is a basic principle that must be followed if cure is to be achieved for most fully malignant cancers. Application of this principle has given gratifying cure rates for colon cancer, for example, and is now embodied in the operations, regional total, and regional subtotal pancreatectomy. Regional pancreatectomy was first described in 1973 when its pathoanatomical basis was presented.4 Subsequent reports have presented additional evidence for the validity of the concept of regional pancreatectomy and indicated, in a preliminary fashion, its therapeutic usef~lness.~~~-~ A movie demonstrating the technique of the operation is registered with the American College of Surgeons Film Librar~.~ Very briefly, regional total pancreatectomy involves removal of the pancreatic segment of portal vein and end-to-end anastomosis without a graft (Figs. 1 and 2). In addition, the base of the transverse mesocolon and a generous margin of soft tissue around the pancreas with regional lymph are removed en bloc with the pancreas and portal vein segment. The regional lymph node dissection includes a meticulous dissection and skeletonization of the porta X/81/0315/1712 $ American Cancer Society 1712

2 No. 6 SURGERY FOR PANCREATIC CA. Fortrier 1713 FIG. 1. The specimen has been removed. Cut ends of superior mesenteric vein and portal vein are indicated by arrows at sides. Just below, the central arrow indicates the skeletonized superior mesenteric artery. hepatis, celiac axis, and superior mesenteric artery with a periaortic node dissection extending from the level of the inferior mesenteric artery upward to the diaphragmatic crura. The vena cava and aorta are skeletonized and all tissues are removed en bloc. The site of transection of the common hepatic bile duct is just below its bifurcation. A subtotal gastrectomy is done. This operation, called regional pancreatectomy Type I, is recommended for all cancers of the pancreas, periampullary region, and for invasive ampullary cancers that show no evidence of spread beyond the immediate pancreatic region and in individuals who are good surgical risks. Involvement of the celiac axis, superior mesenteric artery, or hepatic artery can be treated with arterial resection and reconstruction in addition to the Type I FIG. 2. Portal vein anastomosis in indicated by central arrow. Skeletonized superior mesenteric artery is to the left and celiac axis to the right.

3 1714 CANCER March 15 Supplement 1981 Vol. 41 ~ s ~ m a c n FIG. 3. Sites of transection for regional subtotal pancreatectorny. operation. This is termed a Type I1 operation (Fig. 3). A Type 0 regional pancreatectomy refers to the same operation as the Type I regional pancreatectomy but without removal of the pancreatic segment of portal vein. This is reserved for instances in which the tumor is in the distal body or tail of the pancreas and the region near the portal vein is completely normal. The regional lymph node dissection and soft tissue margin would be as for a Type I procedure. A suitable patient for this procedure has not been encountered to date. Regional subtotal pancreatectomy refers to the operation in which the distal, approximately 5 cm, pancreas is left intact. The arterial supply comes from the splenic artery (Fig. 3). The venous outflow is through the gastroepiploic vessels. A splenectomy is, of course, essential. This procedure is based upon the findings that the pancreatic tail seldom is involved by microscopic multifocal areas of cancer and that lymph near the tail are seldom, if ever, involved by metastatic cancer that originates from a resectable cancer of the head of the pancreas. Emphasis is placed in this operation, as with the regional total pancreatectomy, on the en bloc regional nature of the lymph node dissection, and wide soft tissue margin. The operation is reserved for nondiabetic patients and where the cancer is small, in the head of the pan- creas, and the patient apparently less able to tolerate the diabetic state and nutritional problems seen in some patients after the total pancreatectorny. It is deficient in that the dissection around the superior mesenteric artery and periaortic regions is not as complete as with the regional total pancreatectomy. In poor-risk patients with localized lesions, the author has been carrying out a pancreaticoduodenectomy with an extensive soft tissue and regional lymph node dissection (regional subtotal pancreatectomy Type 0). This operation involves skeletonization of the porta hepatis with transection of the common hepatic bile duct just below the bifurcation of the bile ducts, and skeletonization of the portal vein and hepatic artery en bloc with dissection of the celiac axis lymph and soft tissue medial to the superior mesenteric artery. This is carried out en bloc with a lymph node dissection, which skeletonizes the vena cava, right renal vein, and removes the lymphoid tissue to the right of the superior rnesenteric artery. The dissection extends from the inferior mesenteric artery up to the diaphragmatic crura. Where this operation is not feasible, Is5I radioactive seeds are implanted into the tumor; this is supplemented with external radiation therapy as needed to attain the desired tumor dose. These approaches have been applied by the author in 151 patients treated from Table 1 indicates that the resectability rate was 32% (48/151). Thirty-six patients had a regional pancreatectomy for cancer; three additional patients not included in Table 1 had a regional pancreatectomy for chronic pancreatitis and one for pseudolymphoma. Twelve individuals underwent a resection other than regional pancreatectomy: pancreaticoduodenectomy was done in nine, total pancreatectomy in two, and a dist.1 pancreatectomy performed in one. Of the individuals having a regional pancreatectomy for cancer, 77% had previously been explored and declared unresectable by another surgeon. The type of pancreatectomy was: regional total Type I in 29; Type I1 in seven; and regional subtotal Type I in four patients. The primary tumor was classified as adenocarcinoma of the pancreas in 19 patients. The classification of other tumors included two individuals with islet cell carcinoma and one with hemangiopericytoma of the pancreas. Also included in the latter classification were four individuals with a tumor arising in the ampulla, four in the distal bile duct, four in the duodenum, and two in the periampullary region. There have been no 30-day postoperative deaths during the past two years. The 30-day postoperative mortality rate was 7% (2/29) for regional total Type I, 29% (2/7) for Type 11, and 50% (2/4) for regional sub-

4 No. 6 SURGERY FOR PANCREATIC CA ' Fortner total Type 1: the overall rate was 15% (6/40). The causes of death are shown in Table 2. These six individuals were excluded when estimating the probability of survival. Extent of disease is recorded according to the MSKCC postsurgical staging for cancer of the pancreas. Stage I includes individuals without nodal or distant metastases; Stage I1 includes those with nodal metastases; and Stage 111 disease represents distant metastases. Overall, 27% had Stage I disease, 63% had Stage TI disease, and 10% had Stage 111 disease. For adenocarcinoma of the pancreas, however, only 13% (2/15) were classified as Stage I. Of the 30 individuals with malignant disease who survived the operation, 33% (10/30) are currently alive, 40% (12/30) have died of disease, and 27% (8/30) have died of other causes. If the cause of death was unknown, it was classified as a death with disease. Five of the individuals presently alive had Stage I disease and are living from 6-58 months after regional pancreatectomy. Four living patients had Stage I1 disease and their survivals range from months. One individual with Stage IT1 disease is alive at five months. Two of these ten patients had adenocarcinoma of the pancreas and the remaining eight had other types of cancers (Table 3). An analysis of treatment failures from recurrent disease after regional pancreatectomy is especially illuminating (Table 4). In retrospect, the cancer was too advanced for surgical removal to be curative in most. Resection in these patients was done when the limits of regional pancreatectomy were being defined and they would now be considered only for palliation. Clearly the error is not with the operation but in patient selection. In others, a Type I1 procedure should have been done instead of a Type I. This refers especially to patients whose right hepatic artery originates from the superior mesenteric artery and its course is intimately adjacent to the pancreas. Also, in some patients cancer has been spread when dissecting out the gastroduodenal or hepatic arteries from encompassing or intimately adjacent cancer. This isolated arterial involvement should be resected rather than dissected. Table 5 indicates the cause of death in those eight individuals who died of causes other than apparent recurrent disease. If these eight survival times are considered censored observations, then the two-year estimates of survival distribution are 61% for those with adenocarcinoma of the pancreas and 48% for those with other tumors. If the eight individuals are evaluated as dying of disease, the two-year estimates of survival are 27% and 40%. respectively. During the past year, from February 1979 to February 1980, 26 patients with cancers of the pancreas TABLE 1. Surgical Experience in Malignant Disease: Curative surgery Regional pancre- Palliative Resection atectomy Other surgery rate Pancreas Probable pancreas Ampulla Periampulla Duodenum Common bile duct TOTAL (32%) or periampullary region have been operated upon. A curative resection was carried out in seven with a resectability rate of 27% (7/26). A regional pancreatectomy was performed in three, a pancreaticoduodenectomy with err bloc regional node dissection was done in three, and a distal pancreatectomy was performed in one. Palliative procedures included an 1251 implant in seven patients, a palliative pancreatic resection in two, and a biliary enteric bypass in ten. Discussion There appears to be a relatively small group of patients with cancer of the pancreas or periampullary TABLE 2. Thirty-Day Postoperative Deaths following Regional Pancreatectomy Total pancreatectomy Postop day Type 1 Myocardial infarction 3 Necrosis of common bile duct and thrombosis of portal vein 14 Type 11 Pulmonary embolus 2 Thrombosis of hepatic artery and liver infarction 3 Subtotal pancreatectomy Type 1 Exsanguination via abdominal drains Monilial esophagitis with hemorrhage TABLE 3. Regional Pancreatectomy for Malignant Tumors: Ten Patients Presently Alive Pathologic stage of disease and survival I I1 111 Adenocarcinoma of the pancreas m -- Other tumors m 5 m m

5 17 16 CANCER March 15 Sirpplrrri~nt 1981 Vol. 47 TABLE 4. Causal Factors for Recurrence in Patients Dying of Disease Regional Survival Histology at Case pancreatectomy Date (mos) pancreatectomy Vascular involvement Other 1 Total type I 4/74 6 Adenocarcinoma of pancreas. Extensive local disease: direct invasion of multiple lymph Inferior mesenteric vein destroyed and splenic artery compressed. Common hepatic and duodenal arteries encased by tumor 2 Total type I Adenosquamous carcinoma of the distal common bile duct. Two lymph node metastases Fungating tumor in distal bile duct. Biopsy done and T-tube placed 7 wks earlier at first operation. Spillage of cancer cells almost certain 3 Total type I wlsegment of vena cava removed 1/75 21 Periampullary adenocarcinoma. Extensive soft tissue involvement including renal capsule. Multiple positive lymph Encircled renal vein and involvement 2 cm portion of vena cava. Lateral margin of vena cava resected was involved with tumor 4 Total type I 1/75 6 Adenocarcinoma of pancreas. Extensive soft tissue involvement. Common bile duct and jejunal margins of resection positive. Multiple positive in proximal jejunal mesentery Portal vein invaded posteriorly with jejunal branches of proximal jejunum Classified as palliative at surgery 5 Total type 11 5/75 17 Adenocarcinoma of the pancreas. Perineural invasion. Common bile duct margin positive. Two positive lymph Retropancreatic portion of portal vein and superior mesenteric artery involved by tumor. Segmental resection of both carried out Previous incisional biopsy read as negative 6 Total type I 7/75 6 Adenocarcinoma of pancreas. Infiltration duodenal wall, ampulla, and common bile duct with positive resection margin. Bile contained isolated cancer cells. Multiple positive lymph Positive inferior mesenteric vein 7 Total type I Adenocarcinoma of body of pancreas. Negative lymph Partially excised elsewhere 8 Total type I Duodenal adenocarcinoma with extensive local disease. Multiple positive lymph Unknown cause of death but classified as recurrent disease 9 Total type I 6/76 9 Hemangiopericytoma. Peritoneal implant, abdominal wall involvement. Two positive lymph Tumor thrombus in portal vein 10 Total type I 6/76 30 Adenocarcinoma of pancreas. Direct invasion of two lymph Portal vein surrounded but not invaded by tumor Cancer cells in pleural fluid

6 No. 6 SURGERY FOR PANCREATIC CA. Fortner 1717 TABLE 4. (Continued) Regional Survival Histology at Case pancreatectomy Date (mod pancreatectomy Vascular involvement Other 1 I Subtotal type I 1 1/77 10 Ampullary adenocarcinorna extending into both common and pancreatic ducts. Multiple positive lymph 12 Total type I 11/78 5 Ampullary adenocarcinoma with multiple lymph node metastases Dissection of splenic vein near the tumor Right hepatic artery arising from superior mesenteric artery. Went through tumor area; was dissected off the right hepatic artery Cancer cells may have been spilled in transecting pancreatic or bile ducts region whose cancer is localized at the time a clinical diagnosis is made. Surgical procedures that conform to basic surgical oncologic principles should result in cure of these patients. This appears to be happening with the regional pancreatectomies but the present experience is small owing to the slowness of patient accrual into the program. Collaborative efforts among various hospitals and centers are very much needed for more definitive answers to be obtained. Currently, about one-third of the patients are alive, one-third have died of recurrent cancer, and one-third have died of causes other than recurrent cancer. The operative mortality rate is gratifying in that there have been no 30-day operative deaths for the past two years. Including the earliest cases, this rate was only 7% for the regional pancreatectomy Type I. This operation is recommended for all cancers of the type under discussion unless localized extension requires arterial resection to be carried out when the Type I1 procedure is required. The poor initial results for regional subtotal pancreatectomy are distressing but probably largely preventable by more rigid patient selection in the future. The incidence of recurrent cancer or therapeutic failures should decline sharply. Table 4 shows the pathologic findings in the cases reported here to have precluded cure. More rigid patient selection during the past year has decreased the resectability rate but has avoided resecting patients whose cancer is beyond regional confines. One other area of improvement is clearly possible. This relates to cancers that are localized but involve a segment of artery, i.e., hepatic or superior mesenteric artery. These must have a Type I1 procedure without an attempt being made to dissect the vessel from its encompassing tumor. Furthermore, for any cancer of the head of the pancreas, if the right hepatic artery originates from the superior mesenteric artery, the pancreatic segment of artery should be excised en bloc with the pancreas. Attempts to dissect it fail, for the retropancreatic region is one of the most common areas of macroscopic and microscopic spread of the cancer. One particularly challenging patient during the past year required release of his median arcuate ligament with restoration of hepatic arterial blood supply before the regional pancreatectomy was performed. Prior to this, hepatic arterial blood flow was from the superior mesenteric artery via transpancreatic vessels. The frequency of deaths after 30 days from causes other than recurrent cancer can be decreased. Table 5 reveals the various unusual situations that developed. Some such as the staph. pneumonia may be related to the immune deficient state which many of the patients have.8 Of great interest in this regard is the finding in this laboratory that postpancreatectomy patients are commonly zinc deficient. The latter is reported to result in immune deficiencies and is an area presently under investigation in the laboratory. Hepatic failure and fatal hepatitis could be related to an absence of hepatotrophic factor. Other conditions, TABLE 5. Regional Pancreatectomy for Malignant Tumors- Deaths from Other Causes: Eight Individuals Adenocarcinoma of pancreas Stage I Lung cancer Stage I1 Pulmonary embolus Hepatic failure Hepatitis Hypoglycemia Staph. pneumonia Stage 111 GI bleeding Other tumors Months Months Stage I Inanition 18

7 1718 CANCER March 15 Supplement 1981 Vol. 47 i.e., second primary lung cancer or fatal gastrointestinal bleeding, are fortuitous and unlikely to recur. It is apparent that there is a very strong basis for the belief that regional pancreatectomies will result in significantly increased cure rates. Patients will be selected better, recurrent disease less common, and death from other causes infrequent. REFERENCES 1. Crile G Jr. The advantages of bypass operations over radical pancreatoduodenectomy in the treatment of pancreatic carcinoma. Surg Gynecol Obsret 1970; 130: Cubilla AL, Fitzgerald PJ, Fortner JG. Pancreas cancerduct cell adenocarcinoma: survival in relation to site, size, stage and type of therapy. J Surg Oncol 1978; Forrest JF, Longmire WP Jr. Carcinoma of the pancreas and periampullary region. A study of 279 patients. Ann Surg 1979; 189~ Fortner JG, Kim DK. Regional pancreatectomy. (16-mm movie, color), Fortner JG. Regional resection of cancer of the pancreas. A new surgical approach. Surgery 1973; 73: Fortner JG, Kim DK, Cubilla A, Turnbull A, Pahnke LD, Shils ME. Regional pancreatectomy: en bloc pancreatic, portal vein and lymph node resection. Ann Surg 1977; 186: Fortner JG. Cancer of the pancreas. Letter to the Editor, N Engl J Med 1980; 302: Fortner JG, Kim DK, Hopkins L, Barrett MK, Pinsky CM, Day NK. Immunologic function in patients with carcinoma of the pancreas. Surg Gynecol Obstet 1980; 150: Fortner JG. Surgical principles for pancreatic cancer. In: Nardi GK, ed. Controversial Topics in Surgery, vol. 1. The Hague: Martinus Nijhoff BY Publishers, 1980; in press. 10. Hilaris BS, Anderson LL, Tokita N. Interstitial implantation of pancreatic cancer. Front Radial Ther Oncol 1978; 12: Ihse I, Lilja P, Arnesjo B, Bengmark S. Total pancreatectomy for cancer. An appraisal of 65 cases. Ann Surg 1977; 186: Levin B, ReMine WH, Hermann RE, Schein PS, Cohn I. Panel: Cancer of the pancreas. Am J Surg 1978; 135: Moossa AR, Lewis JH, Mackie CR. Surgical treatment of pancreatic cancer. Mayo Clin Proc 1979; 54: Tryka AF, Brooks JR. Histopathology in the evaluation of total pancreatectomy for ductal carcinoma. Ann Surg 1979; 190: