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Invited Lecture International Session
(Symposium) International Session
(Workshop) Symposium Panel Discussion Workshop International Poster Session
Invited Lecture (JSGS)
Fri. November 2nd   14:00 - 14:40   Room 5: Portopia Hotel South Wing Ohwada A
Invited Lecture-15
 Cutting-edged strategy for borderline resectable pancreatic cancer
Shailesh V. Shrikhande
Division of GI and HPB Cancer Surgery, Tata Memorial Center
Introduction
Conventionally, pancreatic cancers have been classified as resectable (stage I or II), locally advanced (stage III) or metastatic (stage IV). However, over the past few years, a distinct subset of patients with pancreatic cancer has emerged, i.e. patients with borderline resectable pancreatic cancer. BRPC are those which satisfy any one of the following criteria: 1. 180° tumor abutment with the SMA; 2. Short segment (1.5 cm) encasement or occlusion of the PV/SMV; 3. Encasement of short segment of hepatic artery, but not up to celiac axis; 4. Encasement of GDA up to hepatic arterial origin; and 5. 180° tumor abutment with the PV and SMV (1).

Latest AJCC staging system (8th edition), do not consider this subgroup as operable because any venous occlusion or arterial encasement is defined currently as unresectable, thus patients with BRPC have a high risk of being classified as having unresectable disease (Table 1). The ISGPS suggests that preoperative evaluation of resectability should be based on pancreatic protocol contrast enhanced CT scan. However, with recent advances in pancreatic imaging, distinction between resectable (stage I or II) and locally advanced (stage III) disease may be difficult in selected cases. Careful evaluation of CT scan for following details helps to define these tumors better on preoperative imaging. 1). Length of Contact (LC) 2). Circumferential Contact (CC) (Grades I - IV) 3). Venous Deformity (VD) (Grades 0 - 2). With Greater the degree of CC and VD, higher the chances of venous resection.Another important aspect in deciding the appropriate treatment for this subset of patients is the likelihood of ending up in R+ resection. As per our own data, incidence of R1 resection was 7%, in CBD tumors 20% and 57 % in HOP tumors. Posterior and SMA margins are the most commonly involved margins. To overcome this issue, artery first or SMA first approach can used to minimize the chance of R1 resection in selected cases.
ISGPS classification of venous resections:
Type 1: partial venous excision with direct closure (venorraphy) by suture closure;
Type 2: partial venous excision using a patch;
Type 3: segmental resection with primary venovenous anastomosis; andType 4: segmental resection with interposed venous conduit and at least two anastomoses.
ISGPS guidelines on Upfront Venous resection in BRPC (2):
1. On the basis of the currently available evidence suggesting similar survival rates to those reported for patients undergoing a standard resection, there is clear evidence supporting straightforward operative exploration and resection in the presence of reconstructible mesenterico-portal axis involvement.
2. There is currently no evidence for neoadjuvant treatment protocols in BRPC patients with isolated venous involvement, provided technical options of reconstruction are given.
3. After intraoperative evaluation of tumor extent, venous resection is indicated if complete tumor excision (R0) is possible, although this may lead to greater overall rates of intraoperative and postoperative morbidity rates.
4. The ISGPS strongly suggests that these vascular resections should be limited to high-volume centres with experienced surgical and multidisciplinary teams.
ISGPS guidelines on arterial resection in BRPC (2):
1. There is no good evidence that arterial resections during right-sided pancreatic resections are of benefit. Such resections may be harmful with increased morbidity and mortality and should not be recommended on a routine basis.
2. Patients categorized as borderline resectable on the basis of features of arterial involvement seen at imaging, should undergo surgical exploration in order to obtain further verification of any arterial infiltration.
3. In case of verification of arterial involvement, palliative treatment is the standard of care.
4. Respecting patients’ age, grade of comorbidities, tumor biology, and performance status, neoadjuvant approach may be evaluated in addition to the standard of care: There is no level I evidence to recommend neoadjuvant therapy regimens in patients with arterial infiltration; therefore, evaluation of neoadjuvant therapeutic options is only recommended in the setting of prospective trials. If neoadjuvant therapy regimes are applied, an exploratory laparotomy and attempt at resection should be considered in the absence of disease progression after neoadjuvant treatment (distant metastasis) and if patients’ performance status is adequate.
Role of Neoadjuvant Therapy in BRPC
Neoadjuvant therapy may increase the possibility of R0 resection and eradicate systemic micro metastasis and is therefore considered a reasonable approach for treating BRPC. The meta-analysis by Festa V et al, including 10 studies reported that when neoadjuvant treatment of BRPC is administered, 49% of 182 patients achieve R0 resections, and their 2-year survival rate is 41% (3). Neoadjuvant treatment may therefore increase the possibility of R0 resection, leading to longer survival. In another meta-analysis by Tang et al (4), which included 18 studies, they found that 2.8% patients had CR, 28.7% had partial response, 45.9% had stable disease while 16.9% pts progressed on neoadjuvant therapy. 65.3% patients underwent resection and R0 resection was achieved in 57.4% patients. Authors concluded that resection and R0 resection rates in the group of borderline resectable tumor patients after neoadjuvant therapy are similar to the resectable tumor patients, much higher than those in unresectable tumor patients. The survival estimates of borderline resectable tumor patients after neoadjuvant therapy were similar to resectable tumor patients. Patients with borderline resectable pancreatic cancer should be included in neoadjuvant protocols and subsequently be re-evaluated for resection.
In 2017, ISGPS proposed new classification BRPC based on anatomical (SMA and/or CA < 1800 without stenosis or deformity, CHA without tumor contact with proper HA and/or CA, SMV and/or PV including bilateral narrowing or occlusion without extending beyond the inferior border of the duodenum), biological (clinical suspicious for distant metastases or nodal metastases diagnosed by biopsy or PET-CT, CA 19-9 level more than 500 units/ml), and conditional factors (resectable disease based on anatomic and biologic factors but with ECOG status of 2 or more ). Patients are classified as: BR-A (based on anatomic criteria), BR-B (based on biological criteria), BR-C (based on conditional criteria) or a combination of these criteria: BR-AB, BR-BC, BR-AC, BR- ABC. Future studies will define the feasibility of such classification system (5).

Conclusions
BRPC is a distinct subset of pancreatic cancer that blur the distinction between resectable and locally advanced disease. BRPC should be treated with multidisciplinary approaches using neoadjuvant treatment of pancreatic cancer, because it is frequently associated with loco-regional or systemic failure, even if the tumor is resected. Presently, neoadjuvant chemotherapy followed by chemoradiation is the major treatment strategy.

References
1. Shrikhande SV et al; Borderline resectable pancreatic tumors: Is there a need for further refinement of this stage? Hepatobiliary Pancreat Dis Int Vol 10，No 3 ・ June 15，2011.
2. Bokhorn et al; Borderline resectable pancreatic cancer: A consensus statement by the International Study Group of Pancreatic Surgery (ISGPS); Surgery, 155,6.2014.
3. Festa V, Andriulli A, Valvano MR, et al. Neoadjuvant chemoradiotherapy for patients with borderline resectable pancreatic cancer: a meta-analytical evaluation of prospective studies. JOP 2013; 14:618-25.
4. Kezhong Tan et al; Neoadjuvant therapy for patients with borderline resectable pancreatic cancer: A systematic review and meta-analysis of response and resection percentages. Pancreatology xxx (2015) 1-10.
5. Shuji Isaji, Shugo Mizuno, John A. Windsor et al; International consensus on definition and criteria of borderline resectable pancreatic ductal adenocarcinoma 2017. Pancreatology 18 (2018) 2-11.
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