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Borderline Resectable Pancreatic Cancer: Definitions, Management, and Role of Preoperative Therapy

¹ Department of Gastrointestinal Medical Oncology, Unit 426, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030
² Department of Diagnostic Radiology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030
³ Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030
⁴ Department of Pathology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas, 77030
⁵ Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030

Correspondence: Address correspondence and reprint requests to: Gauri R. Varadhachary, MD; E-mail: gvaradha{at}mdanderson.org.

	ABSTRACT

TOP ABSTRACT INTRODUCTION STANDARD PRETREATMENT STAGING... PANCREATICODUODENECTOMY AND... ANATOMICAL CT-BASED DEFINITION... ROLE OF PREOPERATIVE THERAPY... ROLE OF TARGETED AGENTS... CASE PRESENTATIONS POTENTIAL IMPEDIMENTS TO... SUMMARY REFERENCES

 
With recent advances in pancreatic imaging and surgical techniques, a distinct subset of pancreatic tumors is emerging that blurs the distinction between resectable and locally advanced disease: tumors of "borderline resectability." In our practice, patients with borderline-resectable pancreatic cancer include those whose tumors exhibit encasement of a short segment of the hepatic artery, without evidence of tumor extension to the celiac axis, that is amenable to resection and reconstruction; tumor abutment of the superior mesenteric artery involving <180° of the circumference of the artery; or short-segment occlusion of the superior mesenteric vein, portal vein, or their confluence with a suitable option available for vascular reconstruction because the veins are normal above and below the area of tumor involvement. With currently available surgical techniques, patients with borderline-resectable pancreatic head cancer are at high risk for a margin-positive resection. Therefore, our approach to these patients is to use preoperative systemic therapy and local-regional chemoradiation to maximize the potential for an R0 resection and to avoid R2 resections. In our experience, patients with favorable responses to preoperative therapy (radiographical evidence of tumor regression and improvement in serum tumor marker levels) are the subset of patients who have the best chance for an R0 resection and a favorable long-term outcome.

Key Words: Borderline resectable • Pancreatic cancer • Preoperative therapy • management

	INTRODUCTION

TOP ABSTRACT INTRODUCTION STANDARD PRETREATMENT STAGING... PANCREATICODUODENECTOMY AND... ANATOMICAL CT-BASED DEFINITION... ROLE OF PREOPERATIVE THERAPY... ROLE OF TARGETED AGENTS... CASE PRESENTATIONS POTENTIAL IMPEDIMENTS TO... SUMMARY REFERENCES

 
Pancreatic cancer is rarely diagnosed early; two thirds of patients have locally advanced or metastatic disease at the time of diagnosis. For the subset of patients (15%–20%) who present with a potentially resectable tumor, the 5-year overall survival rate for those who undergo a successful pancreaticoduodenectomy (Whipple procedure) is approximately 15% to 20%.¹ It is important to note, however, that the survival rate remains poor for patients who undergo an incomplete (margin-positive) resection, and the available data suggest that the survival duration of these patients is no different from that of patients with locally advanced, surgically unresectable disease treated with chemoradiation.^1,2 Several studies have suggested that in addition to nodal status, margin resection status is a very important prognostic factor (in some studies, the most important) and that a margin-positive resection strongly predicts early recurrence and short survival (Table 1).^3–9

	STANDARD PRETREATMENT STAGING DEFINITIONS OF RESECTABLE AND LOCALLY ADVANCED PANCREATIC CANCER

TOP ABSTRACT INTRODUCTION STANDARD PRETREATMENT STAGING... PANCREATICODUODENECTOMY AND... ANATOMICAL CT-BASED DEFINITION... ROLE OF PREOPERATIVE THERAPY... ROLE OF TARGETED AGENTS... CASE PRESENTATIONS POTENTIAL IMPEDIMENTS TO... SUMMARY REFERENCES

 
There is growing consensus that multidetector CT optimized for pancreatic imaging is the single best test to determine local tumor resectability.^10–13 The CT criteria used at our institution to define a potentially resectable pancreatic tumor include the absence of tumor extension to the superior mesenteric artery (SMA), celiac axis, and common hepatic artery (CHA) and a patent superior mesenteric–portal vein (SMPV) confluence. This definition assumes a standardized approach to surgical resection which allows for en-bloc resection of the superior mesenteric vein (SMV) and/or portal vein (PV) if necessary.¹⁴ Locally advanced, surgically unresectable tumors are defined as those that encase the adjacent arteries (celiac axis, SMA, or both) or that occlude the SMV, PV, or SMPV confluence. In our institution, we use the word encasement to suggest that a low-density tumor involves >180° of the circumference of the vessel and prefer to use the word abutment or involvement to suggest that the tumor involves 180° of the circumference of the vessel.

The main limitation of multidetector CT is its low sensitivity for low-volume hepatic or peritoneal metastases. Studies suggest that up to 20% of patients who are thought to have resectable disease before surgery actually have CT-occult metastatic disease found at laparoscopy or laparotomy.^15–17 In addition, it is important to perform CT before biliary decompression procedures because postprocedure pancreatitis, if it occurs, may prevent detailed anatomical evaluation of tumor-vessel relationships and preclude accurate assessment of the extent of disease on CT.

In contrast to the objective definitions of resectable and locally advanced, unresectable pancreatic cancer described previously, the published literature often contains imprecise definitions of resectability. In addition, one rarely sees a published article that includes a standardized approach to surgical resection and pathologic evaluation of the surgical specimen. The American Joint Committee on Cancer tumor-node-metastasis staging system for pancreatic cancer was revised in 2002 (6th edition) to reflect the fact that most pancreatic cancer patients do not need operative staging and that accurate staging can be determined by high-quality CT.¹⁸ Thus, determination of tumor resectability is no longer a purely surgical judgment made at the time of laparotomy, and objective radiographical criteria can be applied to CT images to accurately determine the extent of disease and resectability status. Pretreatment assessment of resectability is essential to allow the creation of stage-specific treatment programs that emphasize protocol-based therapy. Accurate pretreatment staging is also necessary for any multidisciplinary working group dedicated to the delivery of innovative research-driven patient care.

	PANCREATICODUODENECTOMY AND DEFINITION OF RETROPERITONEAL MARGIN

TOP ABSTRACT INTRODUCTION STANDARD PRETREATMENT STAGING... PANCREATICODUODENECTOMY AND... ANATOMICAL CT-BASED DEFINITION... ROLE OF PREOPERATIVE THERAPY... ROLE OF TARGETED AGENTS... CASE PRESENTATIONS POTENTIAL IMPEDIMENTS TO... SUMMARY REFERENCES

 
Pancreaticoduodenectomy for pancreatic head tumors involves removal of the pancreatic head, duodenum, gallbladder, and common bile duct with or without removal of the gastric antrum (Whipple procedure). It is impossible to determine at the time of surgery, by palpation alone, the relationship of the tumor to the lateral and posterior walls of the SMPV confluence and SMA. Only after transection of the stomach and the pancreas can one appreciate the relationship of the tumor to the SMPV confluence and the SMA. However, once the surgeon has transected the stomach and the pancreas, the only option is to complete the pancreaticoduodenectomy even if the entire tumor cannot be removed. Margin assessment is critical to the determination of the adequacy of resection. The tissue to the right of the proximal 3 to 4 cm of the SMA is referred to as the retroperitoneal margin (some surgeons also refer to this as the mesenteric or uncinate margin). The surgeon should ink this margin in collaboration with the pathologist because specimen orientation may be difficult later as a result of the complex anatomy of this region of the body.¹ The operation is identified as an R0 resection if there is no microscopic tumor found at the margin and as an R1 resection if the retroperitoneal margin or other margin is microscopically positive; this occurs in 10% to 20% of patients despite a grossly complete resection.¹⁴

Retroperitoneal margin positivity is usually due to perineural and lymphatic invasion along the autonomic plexus surrounding the SMA and celiac axis. A grossly incomplete resection is referred to as an R2 resection. Most R2 resections can be avoided by accurate interpretation of the preoperative CT images. It is difficult for a pathologist to differentiate between an R1 and an R2 margin on the basis of gross evaluation of the surgical specimen. Therefore, the surgeon should note the adequacy of the resection (grossly complete or incomplete) in the operative report. The end point for analysis of resectability should be the status of the retroperitoneal margin. For example, to say that a given imaging modality accurately predicted resectability in x% of patients assumes that all patients underwent a complete (R0) resection; this can be determined only through accurate prospective evaluation of surgical margins.

	ANATOMICAL CT-BASED DEFINITION OF BORDERLINE-RESECTABLE PANCREATIC CANCER

TOP ABSTRACT INTRODUCTION STANDARD PRETREATMENT STAGING... PANCREATICODUODENECTOMY AND... ANATOMICAL CT-BASED DEFINITION... ROLE OF PREOPERATIVE THERAPY... ROLE OF TARGETED AGENTS... CASE PRESENTATIONS POTENTIAL IMPEDIMENTS TO... SUMMARY REFERENCES

 
Although the term borderline resectable has been used in the literature and will be used in this article to avoid confusion, many clinicians use the term marginally resectable to denote a clinical stage of pancreatic cancer somewhere between resectable and locally advanced. The National Comprehensive Cancer Network describes borderline-resectable pancreatic head (and body) cancer as tumor abutment of the SMA, severe unilateral SMV or PV impingement, gastroduodenal artery (GDA) encasement up to its origin from the hepatic artery, or colon and mesocolon invasion.¹⁹

In our multidisciplinary practice, patients with borderline-resectable pancreatic cancer include those whose tumors exhibit encasement of a short segment of the hepatic artery, without evidence of tumor extension to the celiac axis, that is amenable to resection and reconstruction; abutment of the SMA involving 180° of the circumference of the artery; or short-segment occlusion of the SMV, PV, or SMPV confluence with a suitable option for vascular reconstruction available because of a normal SMV below and normal PV above the area of tumor involvement. Colon and/or mesocolon invasion is not included in our definition of borderline resectable cancer, both because it is not a quantitative assessment and because, although the procedure may be technically challenging, removal of the mesocolon or colon may be unrelated to the risk for a margin-positive resection.

Objective definitions of resectability (Table 2) are critical for the conduct of clinical trials that involve the use of preoperative or neoadjuvant therapies. A patient with borderline-resectable pancreatic head cancer is at high risk for a margin-positive resection with surgery alone and is usually treated first with systemic therapy, chemoradiation, or both. To apply protocol-based nonsurgical therapies to patients with localized disease, strict, reproducible definitions of the extent of local tumor must be used.

Lu et al.²¹ reported an alternative grading system in which tumor involvement of the PV, SMV, celiac axis, hepatic artery, and SMA is graded on a 0 to 4 scale based on the circumferential contiguity of a tumor and a vessel on CT. No tumor contiguity with a vessel denotes grade 0; in grade 1, the tumor is contiguous with less than one quarter of the circumference of the vessel; in grade 2, the tumor is contiguous with one quarter to one half of the vessel circumference; in grade 3, the tumor is contiguous with one half to three quarters of the circumference; and in grade 4, the tumor contiguity is greater than three quarters of the vessel circumference or there is vessel constriction. Using this system, Lu et al. evaluated 25 patients with pancreatic adenocarcinoma who underwent preoperative pancreatic-phase thin-section helical CT followed by pancreaticoduodenectomy. Surgical results were then correlated with the CT grading system for 80 vessels. All 51 tumors with tumor-vessel relationships graded 0 (48 vessels) or 1 (3 vessels) were resectable, and 7 of the 8 tumors graded 3 were resectable; in contrast, all 14 grade 4 tumors were unresectable. Establishing the resectability threshold between grades 2 and 3, which corresponded to tumor involvement of one half of the circumference of the vessel, yielded the lowest number of false negatives and an acceptable number of false positives for unresectability. The authors reported that such a threshold would have yielded a sensitivity of 84%, a specificity of 98%, a positive predictive value of 95%, and a negative predictive value of 93% for unresectability of the cancer on the basis of the vessels studied. They concluded that tumor involvement of more than one half of the circumference of a vessel is a highly specific predictor of unresectability. However, the authors did not describe a standardized approach to surgery, with or without vascular resection, no pathologic data on resection margin status (R0 vs. R1/2) were reported, and there was no distinction between the involvement of arterial versus venous structures.

In a study by Saldinger et al.,¹⁰ helical CT and CT angiography with 3-dimensional reconstruction were used to prospectively stage 100 patients with periampullary neoplasms. Vascular involvement was graded from 0 to 4, with grade 0 representing no vascular involvement and grade 4 representing total encasement of either the SMA or SMV. Resectability rates for grades 0, 1, 2, and 3 were 96%, 100%, 50%, and 9%, respectively, for an overall resectability rate of 76%. Again, without pathologic correlation, such data, although provocative, are not clinically useful.

In a series reported by Valls et al.,²² the authors commented on the presence of "reticular opacities" abutting the vessels in some of their patients. These were small strands arising from the tumor and abutting an artery. In their study, of eight patients with periarterial stranding, six had resectable disease. We concur that it is not just the degree of circumferential thickening of a vessel that is important, but also the appearance of the surrounding tissue, which can range from dense tissue to periarterial stranding or a grainy appearance, with stranding increasing the chances of a grossly complete resection (R0 or R1). This finding may be even more important in patients who have received preoperative therapy, especially if one believes that the cytotoxic effect of preoperative therapy may be most notable at the periphery of the tumor and the tumor-vessel interface.

Taken together, these studies suggest that tumors with 180° arterial abutment ( 50% circumferential involvement) and those with periarterial stranding rather than dense tissue involving the vessel seem to be most appropriate for inclusion in the definition of borderline-resectable pancreatic cancer because the surgeon is more likely to be able to perform a grossly complete resection (R0 or R1).

Short-Segment Abutment or Encasement of the CHA
Limited encasement of the CHA or the proper hepatic artery (PHA), typically at the GDA origin, is also included in our definition of borderline-resectable pancreatic cancer. This is also referred to as short-segment abutment of the CHA. The hepatic artery is usually redundant, and, therefore, segmental resection and reconstruction are often possible without the need for interposition grafting. It is important to note that short-segment encasement of the CHA may be the only impediment to completion of a margin-negative resection because the more proximal CHA and celiac axis may be surrounded by normal, uninvolved perineural tissue. Such limited involvement of the CHA/PHA at the GDA origin results from cephalad growth of the primary tumor along the GDA; this vessel tethers the tumor to the CHA/PHA and results in limited tumor involvement at that level. Vascular reconstruction of the CHA/PHA with interposition grafting or segmental resection with primary end-to-end anastomosis can be performed in selected patients to enable achievement of an R0 resection. Our small experience with patients in this category has always involved extensive preoperative therapy.

Segmental Venous Occlusion With Option for Reconstruction
In most patients, occlusion of the SMV or SMPV confluence by tumor suggests SMA or celiac axis involvement as well, given the proximity of the SMV to the SMA. It is also rare to see short-segment occlusion of the SMV with sufficient venous flow above and below the occlusion to allow interposition grafting. Therefore, a very small subset of patients with borderline-resectable tumors will have short-segment occlusion of the SMV, PV, or SMPV confluence with a suitable option available for vascular reconstruction. Most patients with SMV or PV occlusion have locally advanced pancreatic cancers that preclude complete tumor extirpation.

In a retrospective study recently published by Tseng et al.¹⁴ from our institution, 141 patients who underwent vascular resection (most were not segmental occlusions) at the time of pancreaticoduodenectomy were compared with patients who underwent standard pancreaticoduodenectomy without vascular resection. Seventy percent of patients in both groups received preoperative chemoradiation. The median overall survival was similar in the two groups (23.4 months in the group that required vascular resection and 26.5 months in the group that underwent standard surgery; P = .177). Somewhat surprisingly, patients with positive and negative margins also had similar overall survival. This was likely due to the use of neoadjuvant therapy and to meticulous margin analysis. Accurate margin analysis ensured that all patients with R1 margins truly had only microscopic disease at the margin. The absence of grossly incomplete resections represents a unique aspect of this study and was undoubtedly the result of extensive multidisciplinary evaluation and treatment of all study patients.

	ROLE OF PREOPERATIVE THERAPY IN PATIENTS WITH BORDERLINE RESECTABLE PANCREATIC CANCER

TOP ABSTRACT INTRODUCTION STANDARD PRETREATMENT STAGING... PANCREATICODUODENECTOMY AND... ANATOMICAL CT-BASED DEFINITION... ROLE OF PREOPERATIVE THERAPY... ROLE OF TARGETED AGENTS... CASE PRESENTATIONS POTENTIAL IMPEDIMENTS TO... SUMMARY REFERENCES

 
Rationale
The rationale for delivering preoperative treatment to patients with borderline-resectable tumors is based on (1) providing an interval of time during which one can gauge the aggressiveness of the cancer and thereby select patients for surgery who have stable or responding disease and, therefore, the greatest likelihood of a favorable oncological outcome—a factor that gains greater importance when the potential morbidity of the operation is high and the survival duration modest; (2) the early treatment of micrometastatic disease, which exists in most patients; (3) giving adjuvant therapy in a neoadjuvant setting, when it is expected to be better tolerated because surgical recovery will not complicate the delivery of chemotherapy or chemoradiation; and (4) the potential for subtle downstaging (tumor destruction, particularly at the periphery) to maximize the potential for an R0/R1 resection.

Neoadjuvant therapy has been studied in patients with potentially resectable pancreatic cancer in single-institution phase II trials.^23–26 To date, the overall survival duration, local control rate, and patterns of tumor recurrence are similar in patients treated with preoperative versus postoperative chemoradiation. However, only recently have clinicians appreciated the importance of accurate pretreatment assessment of resectability, partly because of recent improvements in the quality of cross-sectional imaging. It would be appropriate to assume that if objective criteria for preoperative staging are not used, some patients with borderline-resectable pancreatic cancer will be treated as if they have potentially resectable tumors and some as if they have locally advanced disease. Current and future trials designed to study the effect of systemic therapy with or without chemoradiation on localized pancreatic cancer will greatly benefit from our improved understanding of pancreatic anatomy as it relates to staging, as well as the ability of surgeons to perform complex pancreatic resections for cancer. Such an approach is being evaluated through a prospective cooperative group study (described below).

Eastern Cooperative Oncology Group Study
The main objective of an ongoing phase II multicenter study sponsored by the Eastern Cooperative Oncology Group (ECOG 1200) is to determine the percentage of margin-negative resections in patients with "locally advanced, potentially resectable" adenocarcinoma of the pancreas (this group of patients will include those with borderline-resectable tumors). The study randomizes patients to receive one of two preoperative regimens followed by surgery and adjuvant chemotherapy. Patients are stratified according to SMV/PV occlusion, SMV/PV/SMA/hepatic artery abutment or narrowing, prior surgical exploration, and other factors requiring/supporting preoperative therapy. Arm 1 involves concurrent chemoradiotherapy (50.4 Gy of external-beam radiation over 6 weeks and weekly gemcitabine) followed by surgical resection 4 to 6 weeks after completion of therapy and then postoperative maintenance gemcitabine. Patients on arm 2 receive gemcitabine, cisplatin, and fluorouracil intravenously and then chemoradiation for 6 weeks (50.4 Gy of external-beam radiation over 6 weeks and infusional fluorouracil). Patients in arm 2 also undergo surgical resection 4 to 6 weeks after completion of chemoradiation and then maintenance gemcitabine. This is the first prospective clinical study that will evaluate the role of preoperative chemoradiation in borderline-resectable pancreatic cancer and critically assess margin status.

	ROLE OF TARGETED AGENTS IN PREOPERATIVE THERAPY

TOP ABSTRACT INTRODUCTION STANDARD PRETREATMENT STAGING... PANCREATICODUODENECTOMY AND... ANATOMICAL CT-BASED DEFINITION... ROLE OF PREOPERATIVE THERAPY... ROLE OF TARGETED AGENTS... CASE PRESENTATIONS POTENTIAL IMPEDIMENTS TO... SUMMARY REFERENCES

 
With the increasing availability of potentially active molecularly targeted agents, there is considerable enthusiasm to integrate these agents with cytotoxic chemotherapy and radiation in the preoperative setting. The epidermal growth factor receptor is over-expressed in up to 95% of patients with pancreatic cancer, and activation of the receptor leads to activation of various downstream signaling molecules, mainly the Ras-Raf-MEK-ERK pathway. In an orthotopic nude mouse model, the anti–epidermal growth factor receptor antibody cetuximab inhibits pancreatic carcinoma growth and metastasis via tumor-mediated angiogenesis, and gemcitabine potentiates this effect.²⁷ Cetuximab and the tyrosine kinase inhibitor erlotinib are currently being tested clinically against metastatic pancreatic cancer and would be attractive in the preoperative setting. The Food and Drug Administration recently approved erlotinib in combination with gemcitabine for metastatic pancreatic cancer (Moore MJ, et al, unpublished data).²⁸ Early safety data from a phase I trial of erlotinib, gemcitabine, and radiation for patients with locally advanced, unresectable pancreatic cancer are available (Kortmansky et al, unpublished data).^29,30

Bevacizumab is a humanized monoclonal antibody that prevents the binding of vascular epithelial growth factor to its receptors. The safety and efficacy data reported by Crane et al.³¹ combining bevacizumab plus chemoradiation in locally advanced pancreatic cancer support the further study of bevacizumab with chemoradiation in the preoperative setting in patients with borderline-resectable cancer.

	CASE PRESENTATIONS

TOP ABSTRACT INTRODUCTION STANDARD PRETREATMENT STAGING... PANCREATICODUODENECTOMY AND... ANATOMICAL CT-BASED DEFINITION... ROLE OF PREOPERATIVE THERAPY... ROLE OF TARGETED AGENTS... CASE PRESENTATIONS POTENTIAL IMPEDIMENTS TO... SUMMARY REFERENCES

 
Cases 1 through 4 below provide examples of patients with tumors that fit our definition of borderline resectable and their responses to management that included neoadjuvant therapy. In our experience, the patients with borderline-resectable cancer who have the best oncological results are those whose cancers have shown biochemical (tumor marker) and radiographic responses to chemotherapy and chemoradiation and, therefore, by definition, demonstrate no evidence of disease progression during a lengthy preoperative interval. We do not advocate the use of this type of treatment algorithm in all patients with borderline-resectable pancreatic cancers, and this algorithm is not intended to define the standard of care in this setting. Rather, we describe one approach, based on an evolving experience with multimodality therapy, that is the subject of ongoing evaluation at our institution.

Case 1
A 49-year-old woman presented in 2001 with pain and dyspeptic symptoms and was diagnosed with a pancreatic mass arising in the neck of the pancreas (Fig. 1A). The patient was treated with four preoperative courses of gemcitabine plus cisplatin given every 2 weeks, followed by gemcitabine-based chemoradiation (50.4 Gy in 28 fractions). Serial CT studies were performed at 2-month intervals, and her postchemoradiation, preoperative scans (Fig. 1-B) showed a reduction in the size of the mass but persistent hepatic arterial involvement. Her CA19-9 level, which was 62 U/mL at presentation, normalized to 10 U/mL after chemoradiation. Six months after the initial diagnosis (6 weeks after the completion of chemoradiation), she underwent pylorus-preserving pancreaticoduodenectomy with en-bloc segmental resection of the CHA and PHA, with a saphenous vein interposition graft and tangential resection of the anterior surface of the PV with a saphenous vein patch. The final pathologic findings were a T3N0 ductal adenocarcinoma that invaded the peripancreatic connective tissue to within 1.0 mm of the hepatic artery wall. The tumor did not invade the duodenum or PV. The resection was classified as R0. All 23 lymph nodes removed were negative for tumor. She continues to do well, with no evidence of recurrence at 42 months from the start of therapy and 36 months after pancreaticoduodenectomy.

View larger version (88K): [in this window] [in a new window]   FIG 1. Prechemoradiation and postchemoradiation computed tomographic scans of a patient presenting with short-segment encasement of the common hepatic artery (CHA). (A) Pretreatment scan shows tumor (black arrows) infiltration along the gastroduodenal artery (thick white arrow) and CHA (thin white arrow). (B) Postchemoradiation scan shows reduction in the size of the tumor but persistent hepatic arterial involvement.

View larger version (127K): [in this window] [in a new window]   FIG 2. Prechemoradiation and postchemoradiation computed tomographic scans of a patient with segmental venous occlusion. (A) Pretreatment scan shows a 4-cm, hypodense mass (black arrows) involving the entire uncinate process and extending into the head of the pancreas with complete occlusion of the superior mesenteric vein (SMV; vessel not shown on this image). A venous collateral (thick white arrow) is identified next to the superior mesenteric artery (SMA; thin white arrow), which should not be confused with the SMV. A focal area of tumor extends to and abuts the right lateral border of the SMA. (B) After chemoradiation, a small, recannulated SMV (white arrowhead) is seen within the tumor. At surgery, SMV reconstruction was possible because a suitable segment of patent SMV (not shown in this image) was available for grafting above and below the tumor. (C) Post-chemoradiation coronal view shows a recannulated SMV (white arrowheads) and a patent, normal-caliber SMV above and below the narrowed segment, thus allowing reconstructive surgery. pv, portal vein; sv, splenic vein; imv, inferior mesenteric vein.

View larger version (90K): [in this window] [in a new window]   FIG. 3. Prechemoradiation and postchemoradiation computed tomographic scans of a patient presenting with tumor abutting the superior mesenteric artery (SMA). (A) Pretreatment scan shows tumor in the uncinate process (black arrows) and involving the posterior aspect of the SMA (thin white arrow) for approximately 180°. The superior mesenteric vein (SMV) is not seen in this image because there was a short-segment occlusion of the SMV. (B) After chemoradiation, improvement was seen in the infiltrating tissue (black arrows) directly abutting the SMA (thin white arrow). Despite a marked reduction in the size of the hypodense tumor, arterial abutment was still present. The thick white arrow identifies the SMV.

View larger version (92K): [in this window] [in a new window]   FIG. 4. Prechemoradiation and postchemoradiation computed tomographic scans of a patient with segmental venous occlusion. (A) The pretreatment scan shows tumor (black arrows) surrounding and markedly narrowing the superior mesenteric vein (SMV; white arrowhead). A soft-tissue density comes within millimeters of the adventitia of the superior mesenteric artery (SMA; thin white arrow). (B) After chemoradiation, marked tumor reduction with improved delineation of the tissue planes around the pancreatic head and duodenum is seen. Note the significant improvement in the caliber of the SMV (arrowhead). SMA, thin white arrow.

	POTENTIAL IMPEDIMENTS TO PREOPERATIVE THERAPY

TOP ABSTRACT INTRODUCTION STANDARD PRETREATMENT STAGING... PANCREATICODUODENECTOMY AND... ANATOMICAL CT-BASED DEFINITION... ROLE OF PREOPERATIVE THERAPY... ROLE OF TARGETED AGENTS... CASE PRESENTATIONS POTENTIAL IMPEDIMENTS TO... SUMMARY REFERENCES

Obstructive jaundice frequently complicates pancreatic cancer. Therefore, in jaundiced patients being considered for preoperative therapy, placement of a biliary stent is necessary to allow for normal hepatic function and to resolve symptomatic hyperbilirubinemia. Thus, patients are at risk for stent occlusion during the delivery of preoperative therapy. In our experience, when the duration of preoperative therapy is less than 6 to 8 weeks, stent occlusion is uncommon.³⁶ When the preoperative period exceeds 6 to 8 weeks, occlusion of plastic endobiliary stents may be a frequent cause of emergency room visits and hospitalization in patients undergoing preoperative therapy. We have recently come to favor the insertion of coated expandable metal stents to reduce the rate of stent failure.³⁷ It is important to note that thus far we have found no evidence to suggest that a metal stent complicates subsequent pancreaticoduodenectomy.

	SUMMARY

TOP ABSTRACT INTRODUCTION STANDARD PRETREATMENT STAGING... PANCREATICODUODENECTOMY AND... ANATOMICAL CT-BASED DEFINITION... ROLE OF PREOPERATIVE THERAPY... ROLE OF TARGETED AGENTS... CASE PRESENTATIONS POTENTIAL IMPEDIMENTS TO... SUMMARY REFERENCES

 
In patients with pancreatic cancer, rigorous criteria should be used to define the extent of local tumor growth to allow accurate pretreatment staging and the development of stage-specific therapy. At our institution, we define borderline-resectable tumors as those with tumor abutment of 180° ( 50%) of the circumference of the SMA or celiac axis, short-segment abutment or encasement of the CHA (typically at the GDA origin), or segmental venous occlusion with an option available for venous reconstruction (adequate SMV below and PV above the area of tumor involvement). Patients whose tumors meet these CT criteria undergo neoadjuvant treatment (as part of a clinical trial, whenever possible) with systemic chemotherapy followed by chemoradiation (Fig. 5). Patients with stable or responding disease, by imaging and serum tumor marker levels, then undergo pancreaticoduodenectomy with the knowledge that vascular resection may be necessary. Further prospective clinical trials with well-defined eligibility criteria are necessary to determine the best overall treatment strategy for these patients.

View larger version (15K): [in this window] [in a new window]   FIG. 5. Treatment schema for borderline resectable pancreatic cancer.

	ACKNOWLEDGMENTS

 
Supported by The Lockton Fund for Pancreatic Cancer Research at The University of Texas M. D. Anderson Cancer Center.

Received for publication August 8, 2005. Accepted for publication January 20, 2006.

	REFERENCES

TOP ABSTRACT INTRODUCTION STANDARD PRETREATMENT STAGING... PANCREATICODUODENECTOMY AND... ANATOMICAL CT-BASED DEFINITION... ROLE OF PREOPERATIVE THERAPY... ROLE OF TARGETED AGENTS... CASE PRESENTATIONS POTENTIAL IMPEDIMENTS TO... SUMMARY REFERENCES

 

1. Wolff RA, Abbruzzese JL, Evans DB. Neoplasms of the exocrine pancreas. In: Bast RC Jr, Kufe DW, Pollock RE, et al., eds. Cancer Medicine. 6th ed. Hamilton, Ontario, Canada: American Cancer Society + BC Decker Inc, 2003:1585–614.
2. Li D, Xie K, Wolff RA, Abbruzzese JL. Pancreatic cancer. Lancet 2004; 363:1049–57.[CrossRef][Medline]
3. Millikan KW, Deziel DJ, Silverstein JC, et al. Prognostic factors associated with resectable adenocarcinoma of the head of the pancreas. Am Surg 1999; 65:618–23; discussion 623–4.[Medline]
4. Sohn TA, Yeo CJ, Cameron JL, et al. Resected adenocarcinoma of the pancreas—616 patients: results, outcomes, and prognostic indicators. J Gastrointest Surg 2000; 4:567–79.[CrossRef][Medline]
5. Benassai G, Mastrorilli M, Quarto G, Cappiello A, Giani U, Mosella G. Survival after pancreaticoduodenectomy for ductal adenocarcinoma of the head of the pancreas. Chir Ital 2000; 52:263–70.[Medline]
6. Neoptolemos JP, Stocken DD, Dunn JA, et al. Influence of resection margins on survival for patients with pancreatic cancer treated by adjuvant chemoradiation and/or chemotherapy in the ESPAC-1 randomized controlled trial. Ann Surg 2001; 234:758–68.[CrossRef][Medline]
7. Richter A, Niedergethmann M, Sturm JW, Lorenz D, Post S, Trede M. Long-term results of partial pancreaticoduodenectomy for ductal adenocarcinoma of the pancreatic head: 25-year experience. World J Surg 2003; 27:324–9.[CrossRef][Medline]
8. Takai S, Satoi S, Toyokawa H, et al. Clinicopathologic evaluation after resection for ductal adenocarcinoma of the pancreas: a retrospective, single-institution experience. Pancreas 2003; 26:243–9.[CrossRef][Medline]
9. Kuhlmann KF, de Castro SM, Wesseling JG, et al. Surgical treatment of pancreatic adenocarcinoma; actual survival and prognostic factors in 343 patients. Eur J Cancer 2004; 40:549–58.[CrossRef][Medline]
10. Saldinger PF, Reilly M, Reynolds K, et al. Is CT angiography sufficient for prediction of resectability of periampullary neoplasms?. J Gastrointest Surg 2000; 4:233–7; discussion 238–9.[CrossRef][Medline]
11. Tamm E, Charnsangavej C, Szklaruk J. Advanced 3-D imaging for the evaluation of pancreatic cancer with multide-tector CT. Int J Gastrointest Cancer 2001; 30:65–71.[CrossRef][Medline]
12. Faria SC, Tamm EP, Loyer EM, Szklaruk J, Choi H, Charnsangavej C. Diagnosis and staging of pancreatic tumors. Semin Roentgenol 2004; 39:397–411.[CrossRef][Medline]
13. Kulig J, Popiela T, Zajac A, Klek S, Kolodziejczyk P. The value of imaging techniques in the staging of pancreatic cancer. Surg Endosc 2005; 19:361–5.[CrossRef][Medline]
14. Tseng JF, Raut CP, Lee JE, et al. Pancreaticoduodenectomy with vascular resection: margin status and survival duration. J Gastrointest Surg 2004; 8:935–50.[CrossRef][Medline]
15. Pisters PW, Lee JE, Vauthey JN, Charnsangavej C, Evans DB. Laparoscopy in the staging of pancreatic cancer. Br J Surg 2001; 88:325–37.[CrossRef][Medline]
16. Schmidt J, Fraunhofer S, Fleisch M, Zirngibl H. Is peritoneal cytology a predictor of unresectability in pancreatic carcinoma? Hepatogastroenterology 2004; 51:1827–31.[Medline]
17. Zhao ZW, He JY, Tan G, Wang HJ, Li KJ. Laparoscopy and laparoscopic ultrasonography in judging the resectability of pancreatic head cancer. Hepatobiliary Pancreat Dis Int 2003; 2:609–11.[Medline]
18. Greene FL, Page DL, Fleming ID, et al. AJCC Cancer Staging Manual. 6th ed. New York: Springer-Verlag, 2002.
19. National Comprehensive Cancer Network (NCCN) Practice Guidelines for Pancreatic Cancer. Available at: http://www.nccn.org. 2004 (last accessed 12-2-05).
20. Loyer EM, David CL, Dubrow RA, Evans DB, Charnsangavej C. Vascular involvement in pancreatic adenocarcinoma: reassessment by thin-section CT. Abdom Imaging 1996; 21:202–6.[CrossRef][Medline]
21. Lu DS, Reber HA, Krasny RM, Kadell BM, Sayre J. Local staging of pancreatic cancer: criteria for unresectability of major vessels as revealed by pancreatic-phase, thin-section helical CT. AJR Am J Roentgenol 1997; 168:1439–43.[Abstract/Free Full Text]
22. Valls C, Andia E, Sanchez A, et al. Dual-phase helical CT of pancreatic adenocarcinoma: assessment of resectability before surgery. AJR Am J Roentgenol 2002; 178:821–6.[Abstract/Free Full Text]
23. White RR, Tyler DS. Neoadjuvant therapy for pancreatic cancer: the Duke experience. Surg Oncol Clin North Am 2004; 13:675–84.[Medline]
24. Spitz FR, Abbruzzese JL, Lee JE, et al. Preoperative and postoperative chemoradiation strategies in patients treated with pancreaticoduodenectomy for adenocarcinoma of the pancreas. J Clin Oncol 1997; 15:928–37.[Abstract/Free Full Text]
25. Breslin TM, Hess KR, Harbison DB, et al. Neoadjuvant chemoradiotherapy for adenocarcinoma of the pancreas: treatment variables and survival duration. Ann Surg Oncol 2001; 8:123–32.[Abstract/Free Full Text]
26. Pisters PW, Wolff RA, Janjan NA, et al. Preoperative paclitaxel and concurrent rapid-fractionation radiation for resectable pancreatic adenocarcinoma: toxicities, histologic response rates, and event-free outcome. J Clin Oncol 2002; 20:2537–44.[Abstract/Free Full Text]
27. Bruns CJ, Harbison MT, Davis DW, et al. Epidermal growth factor receptor blockade with C225 plus gemcitabine results in regression of human pancreatic carcinoma growing orthotopically in nude mice by antiangiogenic mechanisms. Clin Cancer Res 2000; 6:1936–48.[Abstract/Free Full Text]
28. Moore MJ Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared to gemcitabine alone in patients with advanced pancreatic cancer. A phase III trial of the National Cancer Institute of Canada Clinical Trials Group [NCIC-CTG] (abstract 1). American Society of Clinical Oncology, Orlando, Florida, May 13–17, 2005.
29. Kortmansky JS, O’Reilly EM, Minsky BD, et al. A phase I trial of erlotinib, gemcitabine and radiation for patients with locally advanced, unresectable pancreatic cancer (abstract 133). American Society of Clinical Oncology, Gastrointestinal Cancers Symposium, Hollywood, Florida, January 27–29, 2005.
30. Iannitti D, Dipetrillo T, Akerman P, et al. Erlotinib and chemoradiation followed by maintenance erlotinib for locally advanced pancreatic cancer: a phase I study. J Clin Oncol 2005; 28:570–5.
31. Crane CH, Ellis LM, Abbruzzese JL, et al. Phase I trial evaluating the safety of bevacizumab with concurrent radiotherapy and capecitabine in locally advanced pancreatic cancer. J Clin Oncol 2006;24:1145–51.[Abstract/Free Full Text]
32. Chen VK, Arguedas MR, Kilgore ML, Eloubeidi MA. A cost-minimization analysis of alternative strategies in diagnosing pancreatic cancer. Am J Gastroenterol 2004; 99:2223–34.[CrossRef][Medline]
33. Levy MJ, Wiersema MJ. Pancreatic neoplasms. Gastrointest Endosc Clin North Am 2005; 15:117–42.[CrossRef][Medline]
34. Eloubeidi MA, Gress FG, Savides TJ, et al. Acute pancreatitis after EUS-guided FNA of solid pancreatic masses: a pooled analysis from EUS centers in the United States. Gastrointest Endosc 2004; 60:385–9.[CrossRef][Medline]
35. Raut CP, Grau AM, Staerkel GA, et al. Diagnostic accuracy of endoscopic ultrasound-guided fine-needle aspiration in patients with presumed pancreatic cancer. J Gastrointest Surg 2003; 7:118–26; discussion 127–8.[CrossRef][Medline]
36. Pisters PW, Hudec WA, Lee JE, et al. Preoperative chemoradiation for patients with pancreatic cancer: toxicity of endobiliary stents. J Clin Oncol 2000; 18:860–7.[Abstract/Free Full Text]
37. Mullen JT, Lee JH, Gomez HF, et al. Pancreaticoduodenectomy after placement of endobiliary metal stents. J Gastrointest Surg 2005; 9:1094–105.[CrossRef][Medline]

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