REVIEW ARTICLE. Left-Sided Pancreatic Cancer. Steven M. Strasberg, MD and Ryan Fields, MD

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1 REVIEW ARTICLE Left-Sided Pancreatic Cancer Distal Pancreatectomy and its Variants: Radical Antegrade Modular Pancreatosplenectomy and Distal Pancreatectomy With Celiac Axis Resection Steven M. Strasberg, MD and Ryan Fields, MD Abstract: Adenocarcinoma of the body and tail of the pancreas is an aggressive malignancy, and classically there have been few survivors after surgery. Radical antegrade modular pancreatosplenectomy and distal pancreatectomy with celiac axis resection are new procedures for these tumors. Radical antegrade modular pancreatosplenectomy is designed to establish an operation with oncologic rationales both for the dissection planes used to achieve negative margins and the extent of node dissection. The extent of lymph node dissection is based on the descriptions of N1 lymph node drainage, and dissection planes are based on fascial planes of the retroperitoneum. Radical antegrade modular pancreatosplenectomy is modular, adjusting the posterior plane of dissection based on the position of the tumor on preoperative computed tomograms. It is also performed right to left to increase visibility and control blood supply early. Radical antegrade modular pancreatosplenectomy is not an extended pancreatectomy but brings the rationales of the modern Whipple procedure to left-sided tumors. In long-term results from our center in 47 patients, there was a high negative tangential margin rate of 89% and an actuarial overall 5-year survival rate of 35.5%. The actual 5-year survival in 23 patients was 30.4%. Distal pancreatectomy with celiac axis resection is a procedure for cancers that have involved the celiac axis. It is based on the fact that resection of the celiac axis may be performed without devascularizing the liver, which then receives its blood supply by the pancreaticoduodenal arcade. It is an extended pancreatectomy. Mature long term results are just becoming available. Results with distal pancreatectomy with celiac axis resection are mixed with some series reporting few or no long-term survivors, whereas others report long-term survival at approximately 20%. Key Words: Pancreatic cancer, radical antegrade modular pancreatosplenectomy (RAMPS), distal pancreatectomy with celiac artery resection (DP-CAR) (Cancer J 2012;18: 562Y570) Adenocarcinoma of the body and tail of the pancreas is a highly malignant tumor. Until the past decade, there were few long-term survivors after surgical resection. For instance, in 1990, it was stated that there were 5 known 5-year survivors with this disease. 1 With advances in detection, staging, and treatment, especially surgical treatment, a small subset of patients with this disease is now being cured. This article will focus on radical antegrade modular pancreatosplenectomy (RAMPS) and distal From the Section of Hepato-Pancreato-Biliary Surgery, Department of Surgery, the Department of Pathology, and the Alvin J Siteman Cancer Center, Washington University in St Louis, MO; and Barnes-Jewish Hospital, St Louis, MO. Reprints: Steven M. Strasberg, MD, Washington University in Saint Louis, 660 S Euclid Ave, Box 8109, Saint Louis, MO strasbergs@wustl.edu. Copyright * 2012 by Lippincott Williams & Wilkins ISSN: pancreatectomy with celiac artery resection (DP-CAR), also called the Appleby procedure. Radical antegrade modular pancreatosplenectomy is a promising technique, which has recently been shown to have a 35% 5-year overall survival (OS). Distal pancreatectomy with celiac artery resection is an extended pancreatectomy for lesions that have spread locally to involve the celiac axis. There have been several reports of this procedure, and its evaluation is continuing. RAMPS History of Left-Sided Pancreatectomy and Development and Rationale of the RAMPS Procedure The first left-sided pancreatectomies were performed in the late 19th century 2 in Europe. The first in the United States was apparently performed by Briggs in St Louis in Until 1999, the standard operation was performed by early ligation of the splenic artery followed by mobilization of the spleen and pancreas, usually from a left-to-right direction, 4 although some authors performed the mobilization right-to-left. 2 Oncologic goals and the strategies to achieve them, namely, the extent of node dissection and the dissection planes used to optimize margin negativity, were not well defined, possibly because most left-sided resections before 1990 were performed for chronic pancreatitis. Radical antegrade modular pancreatosplenectomy (RAMPS) has been performed in our center since Y7 It was designed to establish an operation with oncologic rationales both for the dissection planes used to achieve negative margins and the extent of lymph node dissection. The extent of the lymph node dissection is based on the anatomic descriptions of N1 lymph node drainage from this part of the pancreas by O Morchoe. 8 The anatomic planes for the posterior margin, which is the one that is most often positive, are based on the relationship of the fascial planes of the retroperitoneum to the posterior surface of the pancreas as described by Lei et al. 9 The plane of the posterior dissection is modular and depends on the position of the tumor in relation to the adrenal gland on preoperative computed tomographic (CT) scans as explained below. Radical antegrade modular pancreatosplenectomy is not an extended pancreatic resection. Its intention is to bring the oncologic rationales of the modern Whipple procedure, i.e., N1 lymph node dissection and dissection with the best chance of attaining negative margins, to left-sided pancreatectomies. Anatomic Basis for the RAMPS Procedure Position and Relations As described by Lei et al, 9 the distal pancreas (pancreatic body and tail) lies within the pararenal fascial space (pararenal, meaning near the kidney), that is, behind the peritoneum and in front of a distinct layer of fascia called the anterior renal fascia The Cancer Journal & Volume 18, Number 6, November/December 2012

2 The Cancer Journal & Volume 18, Number 6, November/December 2012 Left-Sided Pancreatectomies: RAMPS and DP-CAR (Fig. 1)). The kidney and the adrenal lie behind the anterior renal fascia in the perirenal space (perirenal, meaning around the kidney), bounded posteriorly by another layer of fascia, the posterior renal fascia. The contents of the perirenal space are contained in a fatty loose areolar tissue, whereas the connective tissue of the pararenal space is much more fibrous in nature. The 2 peritoneal layers of the mesocolon separate on the anterior surface or inferior border of the pancreas, one leaf passing upward on the retroperitoneum and one downward. This explains why the base of the mesocolon is frequently involved by pancreatic tumors. Anteriorly, the stomach is the organ that is most commonly invaded by left-sided pancreatic cancer because the posterior parietal peritoneum overlying the pancreas is usually in contact with the visceral peritoneum covering the posterior wall of the stomach. Laterally, the spleen is frequently involved by tail lesions. The structures that share the pararenal space with the pancreas on its anteroinferior aspect include the duodenum, the splenic flexure of the colon (more laterally), and the root of the mesocolon as noted earlier. The posterior relationships of the pancreas are the most important to the surgeon because the posterior resection margin is the most common site of R1 resection. Posteriorly and superiorly pancreatic tumors invade the splenic artery, the celiac artery, the common hepatic artery, and sometimes, the origin of the left gastric artery. More posteriorly and inferiorly, the superior mesenteric artery, the aorta, and the confluence of the splenic and superior mesenteric veins may be involved. Pancreatic tumors also invade posteriorly through the anterior renal fascia to involve the adrenal and less commonly the kidney or the vasculature of these organs. The RAMPS procedure attempts to maximize the chance of getting negative tangential margins by placing the resection plane behind the anterior renal fascia (anterior RAMPS) when the tumor has not penetrated the posterior capsule of the pancreas on preoperative CT scans, and behind the adrenal gland and Gerota fascia when it has (posterior RAMPS) 5 (Fig. 2). In each case, the goal is to add an extra margin of safety in resecting these tumors, which can spread microscopically beyond their radiographically visible or palpable margins. In each case, the adrenal vein is the intraoperative guide to the position of the margin. In anterior RAMPS, the posterior margin is formed by identifying the adrenal vein at its junction with the left renal vein and following its anterior surface retrograde in a rightto-left direction to the left adrenal gland. The posterior margin continues out on the surface of the adrenal and Gerota fascia. In the posterior RAMPS, the adrenal vein is divided at its termination with the renal vein and elevated along with the adrenal to give the posterior margin. FIGURE 1. Fascial spaces of the retroperitoneum. A indicates left adrenal gland; D, duodenum; K, kidney; P, pancreas; SF, splenic flexure of colon. FIGURE 2. Planes of posterior margin and direction of dissection in different types of distal pancreatectomies. Lymph Node Drainage Both anatomical and pathological studies have been used to determine the propensity of a cancer to metastasize to specific lymph nodes. The anatomical approach uses dissection and injection of markers to identify the primary and secondary nodal drainage stations from particular organs. Pathological lymph node mapping studies use specimens obtained at surgery or autopsy to determine which lymph nodes are invaded in patients who have a particular tumor type. The aim of the RAMPS procedure is to perform a complete N1 lymph node dissection and not resect N2 or N3 node levels. To do so, the position of N1 nodes had to be defined, and we relied on anatomic studies of the lymphatic drainage of the body of the pancreas (Fig. 3) as summarized in a classic review by O Morchoe. 8 The body and tail of the pancreas has 4 nearly equally sized quadrants. Lymphatic vessels traveling from the 4 quadrants connect to lymphatics along the superior and inferior borders of the gland. 8 Small lymph nodes lie along the latter lymphatics. The lymphatic vessels on the superior and inferior borders of the left half of the body and tail drain to splenic nodes in the splenic hilum or gastrosplenic nodes in the gastrosplenic omentum. Lymphatic vessels coursing along the superior and inferior borders of the right half of the pancreatic body drain to the gastroduodenal and infrapancreatic nodes. These 4 sets of lymph nodes form a ring of nodes 8 (Fig. 3). The ring of nodes drain into nodes anterior to the aorta in relation to the celiac and superior mesenteric arteries, but these nodes, which may be thought of as a string of nodes, are not exclusively an N2 node group. Lymphatics from the central part of the pancreatic body enter these nodes directly without first entering a node on the ring. 8 Therefore, they should be considered as N1 as well as N2 nodes. Based on this information, an operation designed to remove N1 nodes should resect both sets of N1 nodes, which we have colloquially referred to as the ring and the string of nodes. Kayahara et al 10 performed pathological mapping of lymph nodes in cancer of the body and tail of the pancreas in 20 patients. Three node groups were involved in more than 20% of patients: nodes along the superior and inferior borders of the pancreas (nodes 11 and 18 in the Japanese system) and the gastroduodenal node (node 8 in the Japanese system) (Fig. 3). These are all resected in the RAMPS operation. Recently, Fujita et al 11 described the results of pathological lymph node mapping in 50 patients with adenocarcinoma of the body and tail of the pancreas. They identified a group of small lymph nodes attached to the pancreas, seen only on histological slides. These nodes were involved by the cancers in approximately 75% of patients. * 2012 Lippincott Williams & Wilkins 563

3 Strasberg and Fields The Cancer Journal & Volume 18, Number 6, November/December 2012 FIGURE 3. Lymphatic drainage of body and tail of pancreas. The ring of nodes are shown in boxes. The celiac and superior mesenteric nodes make up the string of nodes. The gastroduodenal node is node 8 in the Japanese classification, whereas the node chains on the superior and inferior borders are nodes 11 and 18. These nodes are most commonly involved in carcinoma of the body and tail of the pancreas. However, all other lymph node groups were involved very infrequently, usually in less than 10% of patients. The frequently involved small lymph nodes may correspond to the nodes that lie along the superior and inferior borders of the pancreas described in O Morchoe s study, 8 although those were grossly identifiable as nodes. Whether these nodes are exactly the same as those described by O Morchoe is uncertain, but they are certainly removed by RAMPS. The results of Fujita et al are interesting, but it is unclear at present whether they apply to patients in Western countries because the incidence of cancer in nodes that could be macroscopically identified as lymph nodes grossly was so low. In addition, as we will describe, Japanese patients seem to have more well-differentiated tumors than American patients, a fact that also suggests that the disease may differ significantly in virulence in the 2 countries (United States vs Japan). Technique of the RAMPS Procedure Preoperative Preparation A recent abdominal CT scan is used to decide whether to perform an anterior or posterior RAMPS. 5 When a rim of normal pancreas remains posterior to the tumor, the anterior RAMPS is chosen (Fig. 4). When the posterior margin of the tumor contacts or seems to break through the posterior capsule of the pancreas, the posterior RAMPS is selected (Fig. 5). The tumor does not need to be seen to be touching or invading the adrenal for a posterior RAMPS to be selected. It needs only to be seen to have invaded posteriorly out of the pancreas. The principle being applied is that the space between the back of the pancreas and the front of the adrenal is too thin to reliably attain negative margins when the tumor is present in the space. Of course, in some instances, when the tumor is very far to the left in the hilum of the spleen, it is well away from the adrenal. In that, case it is the Gerota fascia and not the adrenal that needs to be removed. The Procedure Staging laparoscopy is performed to detect intra-abdominal metastases, which contraindicate the procedure. A left upper quadrant J incision or Mercedes Benz incision with a longer left limb is used. The abdomen is again explored for evidence of metastases. The lesser sac is entered by freeing the omentum from the colon or by opening through the gastrocolic ligament. The gastrosplenic ligament is divided, taking the short gastric vessels close to the stomach to remove the gastrosplenic node group. The middle colic vein traced to the superior mesenteric vein. The neck of the pancreas is elevated off the superior mesenteric and portal veins. The right gastroepiploic vein may be sacrificed if necessary to display the superior mesenteric vein. A Kocher maneuver is performed and the anterior surface of the left renal vein is exposed for several centimeters. This will be useful later in the procedure when the vein has to be identified on the left side. The lesser omentum is opened, and the right gastric artery is divided. The proper hepatic artery is identified and followed FIGURE 4. Green line shows planned plane of posterior dissection as shown in preoperative CT scan in anterior RAMPS in which the tumor has not penetrated the posterior capsule of the pancreas. Note that the plane is on the anterior surface of the adrenal. Red line shows possible plane when standard distal pancreatectomy is performed without regard to the position of the anterior renal fascia. A indicates left adrenal gland; K, kidney * 2012 Lippincott Williams & Wilkins

4 The Cancer Journal & Volume 18, Number 6, November/December 2012 Left-Sided Pancreatectomies: RAMPS and DP-CAR FIGURE 5. Green line shows planned plane of posterior dissection as shown in preoperative CT scan in posterior RAMPS in which the tumor has penetrated the posterior capsule of the pancreas. A, left adrenal gland. proximally to display the common hepatic and gastroduodenal arteries. The gastroduodenal lymph node (node 8) is mobilized from above downward and left, attached to the superior border of the pancreas, as the common hepatic artery is displayed. The anterior surface of the portal vein is exposed by retracting the gastroduodenal artery (GDA) to the right. The neck of the pancreas is divided using a stapler. A celiac node dissection is performed, taking all the nodes from the crus of the diaphragm superiorly and posteriorly, off the celiac artery and the origins of the left gastric, hepatic, and splenic arteries. In this way, the origin of the splenic artery is exposed from a superior approach as the celiac nodes are dissected downward. The celiac ganglia are not resected. The splenic vein is isolated at its junction with the superior mesenteric vein and divided with a vascular stapler. If tumor invasion is present at this site, a resection of the superior mesenteric vein and/or portal vein is performed and repaired primarily or with a graft. The right border of the dissection is carried downward in the sagittal plane, dividing fat and fibrous tissue until the left side of the superior mesenteric artery is identified (Fig. 6). The artery is followed on its left side, superiorly and posteriorly, down to the aorta. The left sides of both the superior mesenteric and celiac arteries should now be visible down to the point that they come off the aorta. The lymph nodes anterior to the aorta between the celiac artery and superior mesenteric artery and those anterior and to the left of the superior mesenteric artery are taken with this step. The next step continues to develop the right border of dissection, which is now carried in the sagittal plane through the anterior renal fascia onto the renal and adrenal veins (Fig. 6). This step is facilitated by placing a finger on the anterior surface of the left renal vein behind the previously mobilized duodenum. The finger can be palpated from the left side of the dissection posterior to the superior mesenteric artery. Dividing the intervening tissue (anterior renal fascia) will expose the left renal vein. In the anterior RAMPS, the adrenal vein is identified and its anterior surface also becomes part of the posterior plane of dissection, as does the anterior surface of the adrenal gland as it is reached (Fig. 6). The dissection is continued in a posterolateral direction onto the perinephric fat. The superior and FIGURE 6. Anterior RAMPS at completion of dissection. White numbers 1 to 4 show the 4 levels of the sagittal dissection: 1, pancreatic neck; 2, splenic vein; 3, side of celiac and SMA; 4, renal vein. A-C, Subsequent more coronal dissections: along the adrenal vein (A), on the adrenal gland (B), along the surface of Gerota fascia (C). inferior attachments of the pancreas are divided as the dissection proceeds to the left. The inferior mesenteric vein is transected. Division of the lienorenal ligament is the last step in the procedure. In the posterior RAMPS, the adrenal vein is divided at its termination into the left renal vein, and the dissection is carried to the left and posteriorly behind the adrenal gland and onto the surface of the kidney (Fig. 7). After removal from the patient, the specimen is inked at the pancreatic neck margin and on the tangential margins using different colored inks, and a frozen section of the neck of the pancreas is obtained. These tumors may also invade several other organs or tissues in close relationship to the pancreas as described previously (stomach, duodenum, and splenic flexure of the colon). Provided that the disease is local, any of these structures may be resected as in the standard method. The view at the end of the dissection in the 2 procedures is shown in Figures 6 and 7. Laparoscopic Standard Distal Pancreatectomies and Laparoscopic RAMPS Standard distal pancreatectomy has been performed successfully by minimally invasive techniques for more than a decade and has been applied to pancreatic carcinoma in some FIGURE 7. Posterior RAMPS at completion of dissection. Note the deeper level of dorsal dissection compared to Figure 6. * 2012 Lippincott Williams & Wilkins 565

5 Strasberg and Fields The Cancer Journal & Volume 18, Number 6, November/December 2012 centers. A large multi-institutional series found no difference in survival between open and laparoscopic procedures. 12 However, the median follow-up time of 10 months was relatively short; and the survival curve in the laparoscopic group, comprised of only 23 patients, was somewhat immature, with only one patient having reached 5 years of survival. The median survival in both laparoscopic and open groups was 16 months. 12 Theoretically, the RAMPS procedure can be performed laparoscopically. The celiac node dissection and the formation of the posterior plane right on the renal and adrenal veins will be challenging, especially in large, deep patients. Fernandez- Cruz et al 13 reported results of a slightly modified RAMPS procedure performed laparoscopically with good short-term results, but survival was not addressed. Kang et al 14 used a selective approach, using laparoscopic resection when an anterior RAMPS was indicated, but an open approach when a posterior RAMPS was needed. One concern is that Kang et al and Fernandez-Cruz et al seem to have performed a more limited dissection with respect to the renal vein. 13,14 In our technique, we have assured that the plane of the posterior margin is behind the anterior renal fascia by dissecting on to the left renal vein and out along the surface of the adrenal vein. If this step is omitted, it is possible that the plane will be too shallow and anterior to the anterior renal fascia, risking an incomplete resection. The number of patients requiring RAMPS is too small to consider any kind of trial of open versus laparoscopic procedure. Although the benefits of laparoscopy are attractive, the ability to complete the resection routinely without compromising the oncologic goals of the procedure is the primary consideration. Therefore, at present, laparoscopic RAMPS should be attempted in selected patients whose tumor and body habitus are favorable; and the operation should be converted to open if the oncologic principles are not being achieved. patients had negative tangential margins. Four of 47 patients had a positive margin at the pancreatic neck on permanent section, although the frozen section diagnosis was negative for malignancy. In all, 38 (81.0%) of 47 patients had negative margins. Long-Term Survival Mean and median follow-up times of living patients were 44.4 and 26.4 months, respectively. Eighteen patients (38.3%) are alive, and 29 patients (61.7%) have died. Eleven patients (23.4%) are alive without evidence of disease, and 7 patients (14.8%) are alive with disease. Death occurred 1.4 to 74.4 months after surgical resection. Median survival was 25.9 months (Fig. 8). Five-year OS was 35.5% (Fig. 8). Seven patients have lived longer than 5 years. The actual 5-year survival rate of the 23 patients whose surgery was performed more than 5 years before the latest follow-up (June 30, 2010) was 30.4% (7/23). Judged by short-term outcome, number of nodes, tangential margin negativity rate, and long-term survival, these single-center results are very satisfactory. Comparison of RAMPS With Standard Distal Pancreatectomy Pathologic and long-term outcomes of distal pancreatectomies in other case series 11,12,14Y26 are shown in Table 1. There are many problems with comparing studies. Tangential margin positivity rates are often reported, but inking of margins, which makes the margin easier to evaluate by pathologists, does not Results of the RAMPS Procedure Surgical Outcome We have recently reported our results in 47 patients who underwent RAMPS for pancreatic adenocarcinoma between 1999 and The mean (SD) operative time was 243 (94) minutes. Anterior RAMPS was performed in 32 patients and posterior RAMPS with resection of the left adrenal gland in 15 patients. Twenty-four patients underwent resection of 33 adjacent organs or structures in addition to the left adrenal gland. There were no postoperative (30 days) or inhospital deaths. Thirty-one patients (66%) experienced 48 complications. The mean (SD) length of postoperative hospital stay was 11.3 (6.8) days, and the mean (SD) number of days in the ICU was 1.9 (2.5). Pathological Results Tumors ranged in diameter from 1.4 to 9.0 cm, with a mean (SD) of 4.4 (2.1) cm. The mean (SD) number of lymph nodes removed per patient was 18.0 (11.7), with a range of 1 to 60. Twenty-six (55%) of 47 patients had positive lymph nodes in the resected specimen. Approximately one-half of the patients had poorly differentiated tumors, and the other half had moderately differentiated tumors (only one patient had a well-differentiated tumor). Lymphovascular and perineural invasion were common. American Joint Committee on Cancer staging of tumors included 1 stage IA, 2 stage IB, 18 stage IIA, 24 stage IIB, 1 stage III, and 1 stage IV. One patient had adenocarcinoma arising within a cyst, and 2 patients had adenocarcinoma arising within a background of intraductal papillary mucous neoplasm. Forty-two (89.3%) of 47 FIGURE 8. Overall survival results of RAMPS procedure. The curve is censored at 6 years, which is the time point beyond which fewer than 10% of patients have been followed. Hatch marks indicate censored patients within the 6-year follow-up period (reprinted from Mitchem et al 5 ) * 2012 Lippincott Williams & Wilkins

6 The Cancer Journal & Volume 18, Number 6, November/December 2012 Left-Sided Pancreatectomies: RAMPS and DP-CAR TABLE 1. Pathologic and Survival Data (Adapted from Mitchem et al 5 ) First Author (Reference) Mean Tumor Size (cm) Percent N0/N1 Percent Grade W/M / P Percent Margins R0/R1 Mean Number of Nodes Resected Median Survival (Mo) 5-Year Survival (%) Dalton /27 NS R0 only NS 10 NS Johnson 16 NS 29/71 NS NS NS NS 14 Sperti /25 58/29/12 NS NS Kayahara 18 NS 64/36 NS 36/64 NS NS 16 Burcharth /61 23/23/54 77/23 NS 11 28* Shoup /49 0/62/38 72/28 NS Christein /64 2/76/22 78/22 NS Shimada 22 NS 21/79 29w/71mp 75/25 NS 22 (26) 19 Redmond /45 NS 71/29 NS Kooby /54 NS 74/ Kanda 24 NS 49/51 12/76/12K 74/26 NS 13 6 Yamamoto 25 # /50 49/43/7 76/23 NS NS 30 Fujita /60 28w/72mp** 90/ Wu NS NS NS NS 15 0 Kang 14 # /44 18/69/12 87/13 NS Mitchem (Authors series) /55 2/47/49 81/ *Corrected for age-related deaths. Authors estimation from survival of 2 groups. Radial margins were assessed in only 62% of the patients. mp, moderate plus poorly differentiated tumors. Includes 12 patients who had Appleby procedure. None of those patients survived more than 2 years, and the median survival in them was 17 months. Median survival excluding patients who had Appleby procedure was 26 months. Results did not separate well-differentiated tumors from other grades. #Used RAMPS technique in some patients in series. **Ten other tumors were classified as papillary, mucinous, and adenosquamous. Performed as part of a research study involving 2 pathologists who searched for subserosal lymph nodes along the body of the pancreas. Includes results of all 50 patients in paper. These data were supplied in a personal communication by the authors. Eighty-nine percent had negative tangential margins. seem to have been done except in our study. The number of lymph nodes resected is also reported infrequently. Two studies from Asia (one from Korea 14 and the other from Japan 25 ) have reported survival results similar to our own. In both series, some patients were operated on using the RAMPS approach. Excluding 12 patients who had tumors that required resection of the celiac axis (modified Appleby procedure), the results of Shimada et al 22 who used a procedure that was more radical than the posterior RAMPS are similar to ours. One problem with comparing these results to our own is that the reported grade of pancreatic carcinomas tend toward more welldifferentiated tumors in Japan 11,22,24,25 and Korea 14 than in patients in case series from the United States. The survival results of RAMPS seem to be better than the results reported from Western centers using standard distal pancreatectomy in the past, which have reported 5-year survival rates between 10% and 19%. Ideally, the RAMPS procedure should be tested against standard distal pancreatectomy in a randomized trial. However, this goal is likely not attainable because of the disparity between the number of cases available for study and the number required for a randomized trial. The median case per year per center is 3.4 in reported case series 5 (Table 1). To compare 2 treatments with 5-year survival of rates 20% and 35%, group sample sizes of more than 200 patients would be required (i.e., a randomized controlled trial to determine if RAMPS provides that level of superior survival outcome would require a cooperative study involving 25 or more high-volume pancreatic surgery centers over several years. Available data are insufficient to comment on the outcome of laparoscopic RAMPS. DP-CAR History of DP-CAR In 1952, Lyon Appleby, a Canadian surgeon, presented a case of gastrectomy with en bloc resection of the celiac and common hepatic arteries in a patient with gastric adenocarcinoma. 27 In 1960, he presented a 10-year assessment of the operation in his personal series of 19 cases. 28 The liver maintained its arterial blood supply by retrograde flow from the GDA via the pancreatoduodenal arcade and the superior mesenteric artery (SMA) (Fig. 9). Since then, the Western literature has used the eponymous term Appleby procedure to refer to any operation for cancer that involves this strategy for resection of the celiac axis and complete celiac lymph node clearance. As it has been adapted for adenocarcinoma of the pancreas, a noneponymous term for the procedure is being used more frequently. That term is radical distal (or left) pancreatectomy with resection of the celiac axis, often shortened to DP-CAR, which in Asia seems to be the preferred and customary term. Anatomic Basis for DP-CAR Distal pancreatectomy with celiac artery resection acutely occludes the celiac artery, which deprives the liver of its normal * 2012 Lippincott Williams & Wilkins 567

7 Strasberg and Fields The Cancer Journal & Volume 18, Number 6, November/December 2012 FIGURE 9. Collateral pathway for blood supply to liver after DP-CAR. Tumor involves celiac and common hepatic arteries. Lines of transection of these arteries are shown (red dashed lines). Blood supply depends on retrograde flow (red arrows) from the SMA, through the inferior pancreatoduodenal artery and its branches and continues retrograde into the GDA through its branches. From there, the flow is up the proper hepatic artery to the liver. This pathway also must supply the stomach by flow into the right gastric artery from the proper hepatic artery and the right gastroepiploic artery through the GDA. source of blood flow. It also deprives the stomach of blood supply from its normal sources of blood flow. It is well known that celiac artery occlusion from atherosclerotic disease does not usually lead to hepatic infarction because of collateral circulation from the SMA through the pancreatoduodenal arcade. The inferior pancreatoduodenal artery (IPDA) arises from the right side of the SMA 2 to 3 cm from its origin. Its anterior and posterior branches (anterior and posterior inferior pancreatoduodenal arteries) communicate with the anterior and posterior branches of the GDA (anterior and posterior superior pancreatoduodenal arteries), and the whole makes up the pancreatoduodenal arterial arcade that runs within the pancreas close to the concave duodenal sweep (Fig. 9). The IPDA is often absent, in which case, the anterior and posterior inferior pancreatoduodenal arteries arise independently from the SMA. There are many variations of this arterial anatomy, the description of which is beyond the purpose of this paper. However, the critical point is that the arcade is usually sufficient to support flow to the liver when the common hepatic artery is occluded. Because of concern that the flow might be insufficient when celiac artery occlusion is abrupt, as in DP-CAR, some groups have embolized the common hepatic artery with coils days or weeks before the procedure. Others have simply placed a graft between the aorta and the stump of the hepatic artery to avoid the problem of hepatic ischemia. Gastric ischemia has been a problem in some patients in most case series. As the splenic artery is gone, there is no flow from the left gastroepiploic or short gastric arteries, and flow must come retrograde through the pancreatoduodenal arcade and into the right gastric and right gastroepiploic arteries via the GDA. Technique of DP-CAR The technique is essentially that of an extended posterior RAMPS procedure. The celiac artery origin is usually approached from the right after an extensive mobilization of the duodenum. 29 The SMA origin is also usually visible, and the IPDA origin can be injured during the dissection to come around the celiac artery as can the right renal artery. Therefore, great care must be taken to avoid these complications. The celiac artery is divided at its origin from the aorta and the common hepatic artery at its termination, near the point where it branches into the GDA and proper hepatic artery. If coils have been inserted into the common hepatic artery, they are removed to facilitate the closure of the artery. 29 After division of the celiac artery, the artery and the surrounding nerve plexus is resected en bloc with the distal pancreas. Results of DP-CAR Distal pancreatectomy with celiac artery resection was reported in 6 cases in The largest series of DP-CAR for pancreatic adenocarcinoma comes from Hokkaido University in Japan. These authors have presented their results in a series of papers 29,30Y34 In 2007, they reported on 23 patients who underwent this operation between 1998 and No arterial reconstructions were planned; however, 3 reconstructions were necessary owing to intraoperative arterial injury requiring revascularization. All operations included en bloc resection of the celiac artery, common hepatic artery and left gastric artery, the celiac plexus and ganglions, the nerve plexus around the SMA, the crus of the diaphragm and Gerota fascia, the left adrenal gland, the retroperitoneal fat above the left renal vein, the inferior mesenteric vein, and all associated regional lymph nodes. Preoperative coil embolization of the common hepatic artery was described by this group 33 and was performed in 19 patients (83%) to encourage collateralization of hepatic arterial blood flow via the GDA. Portal vein resection was performed in 16 patients (70%). Eight patients (35%) underwent multi-visceral resection (4 gastric resections, 3 colon resections, and 1 jejunal resection). On pathologic analysis, all patients had invasive ductal adenocarcinoma of the pancreas. None had a carcinoma arising within or in association with a mucinous cystic lesion. Following UICC guidelines, all tumors were T3 or T4. Fifteen patients (65%) had lymph node metastases. Twenty-one patients (91%) had an R0 resection. There were no postoperative deaths. The authors report a 48% postoperative morbidity rate, including 4 pancreatic fistulas, and 3 cases of ischemic gastropathy. Two patients required a second surgical procedure (one for ileus and one for intraperitoneal infection). The median survival after resection was 21.0 months, and the estimated 1- and 5- year OS rates were 71% * 2012 Lippincott Williams & Wilkins

8 The Cancer Journal & Volume 18, Number 6, November/December 2012 Left-Sided Pancreatectomies: RAMPS and DP-CAR and 42%, respectively. Patterns of recurrencewere not reported. These results seem very encouraging. However, there are a number of problems in evaluating the data. Importantly, the Kaplan-Meier survival curves seem immature, with only one patient having reached 5 years of survival. 33 In subsequent reports from this group, 5-year survival rates of 17% 34 and 25% 29 have been reported in this enlarging case series, suggesting that the 5-year OS rate of 42% in the earlier report was overly optimistic. Inking of the resected specimen does not seem to have been routine. Actual invasion of the celiac and/or hepatic arteries was present in only 2 patients but was more uniformly present in surrounding nerve plexuses. Hishinuma et al 35 from the Tochigi Cancer Center in Japan reported on 7 patients who had DP-CAR in an overall series of 25 patients who underwent distal pancreatectomy for adenocarcinoma from 1987 to Portal vein resection was performed in one patient (14%). Six patients (86%) required multi-visceral organ resection. All patients had ductal adenocarcinoma of the pancreas. All tumors were T3 or T4. Four patients (57%) had lymph node metastases. Four patients (57%) had an R0 resection. There were no postoperative deaths. The authors report a 43% postoperative morbidity rate, including one pancreatic fistula. Survival rates are not determinable from such small numbers. All patients have now died, but one survived approximately 75 months and another survived approximately 45 months. Shimada et al 22 reported 12 patients who had DP-CAR as part of a series of 88 patients who had a radical distal pancreatectomy similar to the posterior RAMPS. None of the 12 patients lived more than 2 years. A number of other centers have reported series with fewer cases of DP-CAR. 36Y39 Evaluation of the Literature on DP-CAR Distal pancreatectomy with celiac artery resection, unlike RAMPS, is a true extended pancreatectomy. At present, it is necessary to have serious reservations regarding the efficacy of this procedure. Few patients have achieved long-term survival. Our enthusiasm for new extended pancreatic procedures should be tempered by the prior collective experience of extended nodal and arterial resections for cancers of the head of the pancreas. Therefore, DP-CAR should be conducted with meticulous collection of data and detailed reporting. Of utmost importance in interpreting results of DP-CAR is documentation of pathologic evidence of celiac arterial invasion. This defines the necessity of the operation: if there was no invasion of the celiac artery, was the operation necessary? Of course, preoperative and intraoperative determination of tumor invasion into the celiac artery can be difficult, if not impossible. However, it is critically important to report these data in such series. For example, Hirano and Kondo report 18 (78%) of 23 patients with perineural invasion of the nerve plexus surrounding the celiac artery (CA), CHA, splenic artery (SA), and/or SMA; but only two (9%) of these patients had intramural invasion of the CA or CHA. It is unclear if clearing the perineural tissues around the arteries would have been sufficient for an R0 resection, similar to the strategy commonly used to clear the SMA during a pancreaticoduodenectomy for adenocarcinoma of the head of the pancreas. Central to the question of the necessity of arterial resection is the preoperative evaluation of patients with adenocarcinoma of the body of the pancreas. In the reported DP-CAR literature, this evaluation is not presented in much detail. It would be important to correlate preoperative radiographic findings and postoperative pathologic findings. Inking of resection specimens is important in determining whether R0 resection has been attained. As discussed earlier, it may be difficult or impossible to determine the necessity of arterial resection with a high degree of certainty preoperatively, resulting in a low rate of true arterial involvement, but a high degree of R0 resections. Most of the reported series do not include patterns of recurrence in their analyses. It is important to determine if DP-CAR results in improved local control. This is especially relevant given the low rate reported of true arterial invasion. Might a lesser operation that includes dissection of the perineural tissues from the celiac axis, followed by adjuvant radiation therapy, lead to similar results? Because designing and executing a trial to rigorously answer this question is likely impossible, obtaining and documenting recurrence and adjuvant treatment information in these patients is very relevant. Patients with localized carcinoma of the body of the pancreas including those with involvement of the celiac axis should be approached with curative intent, when possible. In such patients, we currently prefer to begin with downsizing regimens of chemotherapy, often with radiation therapy, for several reasons. First, the current era of chemotherapy, including FOLFIRINOX 40 and other aggressive regimens, is effective in achieving tumor regression, which may obviate the need for arterial resection. Second, chemotherapy allows for patients with aggressive biology to manifest metastatic spread before surgery, thus sparing them the morbidity of aggressive surgery with no potential for benefit. Patients with locally advanced nonmetastatic tumors are then appropriately selected for surgery. 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