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“laparoscopy,” “pancreatectomy,” and “pancreatic neoplasm.” These terms and combinations of them, as well the terms “pancreas,” “adenocarcinoma,” “distal pancreatectomy,” “robotic,” and “minimally invasive surgery,” were used in text word searches. The “related articles” function was utilized to broaden the search. The reference lists of selected articles were also examined to identify relevant studies not discovered during the database searches. Articles were selected for final review if they reported at least 10 cases of minimally invasive DP for pancreatic adenocarcinoma. Each reviewed article was given a final grade of recommendation using the Grades of Recommendation, Assessment, Development, and Evaluation system.

A flow chart illustrating the literature review is given in Figure 15-6. The initial search yielded 60 articles published between January 1990 and March 2013. Of these, 17 were excluded because they were not relevant based on a review of the title and abstract. Of the remaining 43 abstracts, 20 were excluded because they did not pertain to DP for resectable adenocarcinoma of the body or tail of the pancreas, and three were excluded because they were abstracts that were presented at meetings and yielded no subsequent manuscript. A total of 20 articles were reviewed in detail; of these, 14 were excluded because they did not meet the inclusion criteria after further review (two articles), reported on a duplicate patient cohort (one article), or reported on fewer than 10 patients with histologically proven adenocarcinoma (11 articles). Thus, only six studies were identified and reviewed in

detail.1,2,3,4,5,6

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FIGURE 15-6 CONSORT diagram.

FINDINGS

The findings of the six studies reviewed in detail are summarized in Table 15-2. Of these six studies, five were single-center reviews, and one was a

multicenter review. Only two of the studies specifically examined the use of minimally invasive DP in the setting of adenocarcinoma.1,5 Both of these, one of which was the multicenter review, compared outcomes in adenocarcinoma patients undergoing minimally invasive DP or open DP. Of the other four studies, two included subgroup analyses of adenocarcinoma patients, and two combined data from patients with all histologic indications in their analyses. Thus, four studies provided specific data about the use of minimally invasive DP in the setting of adenocarcinoma.

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TABLE 15-2 Six Studies Meeting All Inclusion Criteria

Note: All studies were retrospective. The study by Kooby et al involved multiple institutions.

Abbreviations: CI, confidence interval; LDP, laparoscopic distal pancreatectomy; LOS, length of stay; MIDP, minimally invasive distal pancreatectomy; NA, not applicable; ODP, open distal pancreatectomy; PDAC, pancreatic ductal adenocarcinoma; SD, standard deviation; SEM, standard error of the mean.

NB: Metrics provided may reflect those of the entire group studied, and do not necessarily reflect those of pancreatic cancer patients alone.

P.264 The mean number of pancreatic adenocarcinoma patients in the six studies was 21 (range, 13 to 28 patients). The studies’ mean operative time for minimally invasive DP was 225 minutes (range, 159 to 310 minutes). The mean operative blood loss volume for minimally invasive DP was 430 mL (range, 150 to 1300 mL). The mean margin positivity rate of patients undergoing LDP was 11.8% (range, 3% to 26%). The mean and median numbers of lymph nodes harvested using minimally invasive DP ranged from 6 to 14.5.

Together, the six studies’ findings suggest that minimally invasive DP is favorable to ODP in terms of perioperative aspects including operative time, blood loss, and length of hospital stay for a variety of diagnoses. The one study that compared minimally invasive DP and ODP for adenocarcinoma revealed no significant difference in operative time between the two approaches. Two studies showed that patients undergoing minimally invasive DP had significantly less blood loss than those undergoing ODP. Three studies reported that patients undergoing minimally invasive DP for all indications had an overall shorter length of hospital stay than those undergoing ODP, and two studies comparing outcomes in adenocarcinoma patients specifically reported that the length of hospital stay for patients undergoing minimally invasive DP was significantly shorter than that for patients undergoing ODP. In the one comparative study that evaluated it, adjuvant therapy completion rates of patients undergoing minimally invasive DP (89%) or ODP (85%) did not differ significantly.

The reviewed studies’ findings suggest that short-term surrogate metrics of oncologic outcomes, including margin positivity rate and lymph node yield, do not differ between minimally invasive DP and ODP. Neither of the two studies that compared the margin positivity rates of patients undergoing ODP to those of patients undergoing minimally invasive DP revealed a significant difference between the groups. Furthermore, the two studies that compared the outcomes of patients who underwent minimally invasive DP or ODP for adenocarcinoma did not demonstrate a significant difference in the number of lymph nodes harvested between the minimally invasive DP and ODP groups.

Overall, the six studies provide some evidence suggesting that minimally invasive DP and ODP result in equivalent survival. Five studies reported at least some survival information for patients undergoing minimally invasive DP for adenocarcinoma. Two of these studies compared survival outcomes of patients undergoing minimally invasive DP to those of patients undergoing ODP. In one comparative study, which had a median follow-up time of 10 months, Kooby et al reported that patients undergoing minimally invasive DP or ODP both had a median overall survival duration of 16 months (p = 0.71). A multivariate analysis in this study that included all 212 patients undergoing minimally invasive DP or ODP revealed that resection method did not significantly affect survival. In the other comparative study, Magge et al found no difference in overall propensity score-adjusted survival between the minimally invasive DP and ODP cohorts (hazard ratio, 1.11; 95% confidence interval, 0.47 to 2.62; p = 0.80). In this study, the rates of local recurrence as the sole evidence of progression for patients undergoing minimally invasive DP (7%; 2 of 28 patients) and patients undergoing ODP (3%; 1 of 34 patients) did not differ significantly (p = 0.59).

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Three studies described survival outcomes for only patients undergoing minimally invasive DP. Marangos et al reported that the median survival duration following minimally invasive DP for adenocarcinoma was 19 months (range, 0.5 to 108 months). In the study by Song et al, the 1- and 2-year overall survival rates were both 85.2%; three of the patients in the study developed distant and regional recurrences and died. Fernandez-Cruz et al reported a median survival time of 14 months. In this study, three patients developed distant and local recurrences and died within 1 year.

CONCLUSION

Although multiple centers have described their experiences with minimally invasive DP, there is only limited evidence regarding the oncologic results of this procedure in the setting of pancreatic adenocarcinoma. At best, minimally invasive DP is feasible in the setting of pancreatic adenocarcinoma and offers the typical benefits of a minimally invasive approach in terms of hospital stay and operative blood loss. However, the approach has no obvious advantage over ODP with regard to short-term surrogates of oncologic metrics, such as the number of lymph nodes harvested and margin positivity rate. Limited retrospective comparative data, at least those from studies with followup times of less than 1 year, indicate no difference in overall survival between patients undergoing minimally invasive DP or ODP. To date, the multicenter study by Kooby et al is the best example of the additional studies that compare minimally invasive DP and ODP and specifically assess mediumand long-term overall and recurrence-free survival that are needed before stronger conclusions about the use of minimally invasive DP or ODP in this population can be made. As surgeons’ comfort and experience with minimally invasive DP increases, a formal randomized trial specifically assessing outcomes in adenocarcinoma patients following minimally invasive DP or ODP may become feasible.

Current evidence suggests distal pancreatectomy using a minimally invasive approach among patients with resectable adenocarcinoma of the body/tail of the pancreas is feasible, safe, and associated with favorable short-term perioperative outcomes and surrogates for oncologic outcomes.

REFERENCES

1.Kooby DA, Hawkins WG, Schmidt CM. A multicenter analysis of distal pancreatectomy for adenocarcinoma: is laparoscopic resection appropriate? J Am Coll Surg 2010;210(5):779-785, 786-787.

2.Fernandez-Cruz L, Cosa R, Blanco L, et al. Curative laparoscopic resection for pancreatic neoplasms: a critical analysis from a single institution. J Gastrointest Surg 2007;11(12):1607-1621; discussion 1621-1622.

3.Song KB, Kim SC, Park JB, et al. Single-center experience of laparoscopic left pancreatic resection in 359 consecutive patients: changing the surgical paradigm of left pancreatic resection. Surg Endosc 2011;25(10):3364-3372.

4.Marangos IP, Buanes T, Røsok BI, et al. Laparoscopic resection of exocrine carcinoma in central and distal pancreas results in a high rate of radical resections and long postoperative survival. Surgery 2012;151(5):717-723.

5.Magge D, Gooding W, Choudry H, et al. Comparative effectiveness of minimally invasive and open distal pancreatectomy for ductal adenocarcinoma. JAMA Surg 2013;148(6):525-531.

6. Jayaraman S, Gnonen M, Brennan M, et al. Laparoscopic distal pancreatectomy: evolution of a technique at a single institution. J Am Coll Surg

2010;211(4):503-509.

2015;261:12-17.

2. Zureikat AH, Moser AJ, Boone BA, et al. 250 robotic pancreatic resections: safety and feasibility. Ann Surg

2013;258:554-559.

3. Croome KP, Farnell MB, Que FG, et al. Total laparoscopic pancreaticoduodenectomy for pancreatic ductal adenocarcinoma: oncologic advantages over open approaches? Ann Surg 2014;260:633-640.

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Operative Standards for Cancer Surgery provides a complete outline of the preoperative staging and intraoperative management of patients with pancreatic cancer. This manual provides a foundation of knowledge which should accompany all surgeons in the outpatient clinic, the operating room, and perhaps most importantly, one’s weekly multidisciplinary conference. An institution’s multidisciplinary working group should achieve consensus on how patients are staged and optimal stage-specific management (on and off of a clinical trial). Institutional consensus on staging and stage-specific therapy is necessary to achieve the best possible patient outcome. Such consensus is not achieved without some controversy and oftentimes vigorous debate. Operative Standards for Cancer Surgery provides information necessary to appropriately frame the most common controversies in the management of patients with pancreatic cancer. As a further aid to the surgeon, I will comment on a few of those issues in the paragraphs below.

Two of the most frequently debated topics with regard to intraoperative management include the use of laparoscopy and the role for intraoperative evaluation of local tumor resectability. At our institution, we utilize staging laparoscopy as an extension of the “time out” procedure—performed at the time of planned definitive pancreatic resection. In general, laparoscopy is not performed as a separate staging procedure but is performed before the abdomen is opened for definitive resection in virtually all patients. Laparoscopy as an extension of the time out procedure allows abdominal exploration (laparoscopically) to be performed in all patients, allows the application of uniform staging to all patients by carefully evaluating the surface of the liver and all peritoneal surfaces, and clearly provides a level of abdominal exploration which would not occur if it was attempted after opening the abdomen (through, for example, a standard upper midline incision is usually employed). Historically, the use of laparoscopy was somewhat controversial, but that was largely in an era when laparoscopic equipment was not available in every operating room and therefore the debate over which patients should undergo laparoscopy was more compelling. In the current era of wide availability of laparoscopic equipment in virtually every operating room, simply placing a scope in the supraumbilical location prior to opening the abdomen, in all patients, is hard to argue with; such uniform staging is also critically important to the conduct of clinical trials. In contrast to laparoscopy, which evaluates the peritoneal cavity for subcentimeter peritoneal, mesenteric, and surface liver metastases (which are not well seen on preoperative imaging), the assessment of local tumor resectability is more accurately defined on preoperative imaging than intraoperative assessment. Prior to the advent of high-quality cross-sectional imaging with computed tomography or magnetic resonance imaging, surgeons would oftentimes evaluate local tumor resectability (with regard to tumors of the pancreatic head and uncinate process) by Kocherizing the duodenum and manually palpating the relationship of the tumor to the superior mesenteric artery (SMA). This is a grossly inaccurate method of assessing tumor-artery abutment or encasement. An equally inaccurate method of assessing a tumor vessel relationship is to develop the plane of dissection anterior to the SMV-portal vein confluence

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and posterior to the pancreatic neck. If this plane was successfully developed, surgeons historically were reassured that (later in the operation) after pancreatic, gastric, and biliary transection, the tumor could be

successfully separated from the SMV-portal vein confluence. The fallacy of this assumption was that tumors which were inseparable from the posterior or posterolateral aspect of the SMV or portal vein were not detected until the surgeon had already committed to resection. Contemporary cross-sectional imaging can alert the surgeon to the need for venous resection preoperatively, and the preoperative assessment of both arterial and venous abutment or encasement is a fundamental element of preoperative staging. In 2014, there is little role for intraoperative assessment of local tumor resectability; in the vast majority of patients, the surgeon should not be surprised by any aspect of local tumor anatomy, as this should have been apparent on preoperative evaluation. Again, the importance of a multidisciplinary conference in reviewing/re-reviewing such findings cannot be overstated.

The most important margin of resection during the removal of a pancreatic head or uncinate process cancer is the SMA margin. Although some may disagree, in the opinion of this reviewer, there is little excuse for not exposing the SMA at the time of pancreaticoduodenectomy. Complete exposure and visual identification of the SMA is critically important to prevent SMA injury, to individually ligate the origins of the inferior pancreaticoduodenal arterial (IPDA) branches, and to obtain an optimal oncologic margin of resection. Once the uncinate process is separated from the jejunal branch of the SMV, by dividing the small venous tributaries to the pancreas, the SMA should be identified along its anterior and right lateral borders (at the level of the uncinate process just proximal to the jejunal branch of the SMV, which typically courses posterior to the SMA). Identification of the SMA at that level is the single most important technical skill which trainees, who are learning this operation, should acquire. It is unlikely that the SMA will be inadvertently injured if it is identified and easily seen within the operative field. If there is an iatrogenic injury of the SMA and it is exposed and identified, it can be safely repaired. Further, postoperative hemorrhage, if it occurs within the first 24 hours of surgery, is virtually always due to inadequate control of the IPDAs. This can consistently be prevented by identifying the origin of the IPDAs arising from the SMA and securing them appropriately. Lastly, as systemic therapies for patients with pancreatic cancer improve, local disease control will become even more important. Removal of all tumors to include perineural extension at the level of the SMA is the most important element with respect to local disease control. All surgeons performing pancreaticoduodenectomy should be comfortable in exposing the SMA, ligating the origin of the IPDAs, and removing all soft tissue and autonomic neural tissue to the right and posterior to the SMA.

Controversy persists regarding whether or not to submit the hepatic duct transection margin and the pancreatic transection margin for frozen section analysis. It is our practice, when performing pancreaticoduodenectomy, to always send the hepatic duct and pancreatic transection margins (as en face sections of the margins) for frozen section evaluation. What we do with this information may

P.270 vary based on the complexity of the operation and the oncologic profile of the patient. In the vast majority of situations, we prefer to leave the operating room with no evidence of high-grade dysplasia or invasive cancer at either of these two margins. Obviously, if the patient has undergone an extensive high-risk operation associated with an unanticipated high level of blood loss or a lengthy operative time, it may not be appropriate to chase a suspected positive hepatic duct or pancreatic transection margin. Similarly, if one is in the very rare situation of having an incomplete gross resection of the primary tumor, considering re-resection of a microscopically positive hepatic or pancreatic transection margin may make little sense. However, if one is dealing with a favorable oncologic situation in an otherwise routine pancreaticoduodenectomy, we would re-resect either of these margins back to negative status. When performing distal pancreatectomy for tumors of the pancreatic body, the situation is even more complicated if a positive margin would require total pancreatectomy. Therein lies the rationale for a very detailed preoperative assessment to include a thorough discussion of this possibility with the patient and his or her family prior to operation. For relatively small tumors involving the pancreatic neck, it may be somewhat unclear as to whether the patient would be best served by an extended distal pancreatectomy or

an extended Whipple procedure. In such situations, we would typically divide the pancreatic neck on the right (close to the pancreatic head) first and obtain a frozen section of that transection margin. If that margin should return negative, then either a middle segment pancreatectomy or a distal pancreatectomy would be the operation of choice. However, if that margin should return positive, then the patient would best be managed with an extended Whipple procedure. Again, an understanding of this possible intraoperative challenge prior to surgery and a thorough discussion with the patient is very important.

When managing large pancreatic body tumors with distal pancreatectomy, there is growing enthusiasm for the technique described as radical antegrade modular pancreaticosplenectomy (RAMPS). Another way to think of this operation is to review the steps involved with removal of a tumor in this location. While RAMPS emphasizes removal of all neural and soft tissue to the left of the SMA to ensure a negative margin at that location, there are other important elements involved in the removal of large tumors of the pancreatic body which may be in proximity to the celiac axis or SMA and associated with splenic vein occlusion resulting in sinistral portal hypertension. We typically begin such operations by entering the lesser sac and exposing the anterior surface of the SMV. We then completely take down the ligament of Treitz to prevent inadvertent injury of the proximal jejunum (at the ligament of Treitz) when incising the visceral peritoneum along the inferior border of the pancreas. Typically, one would enter or incise the base of the transverse colon mesentery just to the left of the middle colic vessels. In doing so, one can easily injure the proximal jejunum if the ligament of Treitz had not been taken down completely. We then widely open the lesser omentum and remove the nodal tissue anterior to the proximal common hepatic, left gastric, and splenic artery origins. The splenic artery is then encircled and ligated but not divided.

P.271 If access to the proximal splenic artery is viewed as impossible, one may consider preoperative splenic artery embolization. Once the splenic artery is ligated, we then take down the splenic flexure of the colon, mobilize the distal pancreas and spleen out of the left upper quadrant, and divide all of the short gastric vessels. At this point in the operation, we have now effectively eliminated all arterial inflow into the spleen. We then return to the midline and divide the pancreas anterior to the SMV-portal vein confluence, assuming that this represents an area of normal pancreas being to the right, or proximal to, the area of the primary tumor. The pancreas can be divided either with the stapling device, in which case we usually use a bioabsorbable staple line reinforcement (Gore-Tex or Seamguard pledgets), or with cautery or scalpel anticipating a suture closure. With the pancreas divided (and having ligated the splenic artery), one can then divide the splenic vein. Obviously, if the splenic vein was occluded by the tumor, division of the pancreas and the splenic vein could have occurred before mobilization of the distal pancreas and spleen to facilitate transection of the short gastric vessels. If the splenic vein is patent, then it is helpful to eliminate all arterial inflow into the spleen before the splenic vein is divided. Division of the splenic vein is made much easier by transection of the pancreas. With the pancreas divided, exposure of the junction of the splenic-SMV-portal veins is quite good and we usually divide the distal splenic vein with the endovascular stapler. With the splenic vein divided, exposure to the celiac bifurcation is greatly enhanced and the splenic artery can then be divided. Either before or after division of the splenic artery, the SMA is exposed posterior to the SMV. Similar to performing a pancreaticoduodenectomy, exposure of the SMA is critically important, prevents iatrogenic injury, and optimizes the oncologic margin as initially described in the RAMPS procedure. Frequently, the left gastric artery arises fairly proximal on the celiac artery and often courses cephalad to the pancreatic body tumor. Even in those cases where celiac resection is required, one can oftentimes remove the celiac artery distal to the origin of the left gastric artery, thereby preserving this artery. When performing a distal subtotal pancreatectomy, it is preferred, whenever possible, to preserve the left gastric artery; this preserves arterial inflow to the proximal stomach, which may prevent ischemic gastropathy and thereby preserve normal gastric emptying. In those patients who require celiac resection (Appleby procedure), preservation of the left gastric artery is important unless the celiac artery is revascularized.

I would like to congratulate the authors of Operative Standards for Cancer Surgery and hope that most of the

procedures and recommendations will be put into practice by the many readers of this manual.

Douglas B. Evans, MD

Pancreatic Cancer Program

Department of Surgery

Medical College of Wisconsin

Milwaukee, Wisconsin

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Pancreas Synoptic Report

Operative Staging

Extent of Dissection and Lymphadenectomy