How to treat borderline resectable pancreatic cancer: current challenges and future directions

How to treat borderline resectable pancreatic cancer: current challenges and future directions Abstract Borderline resectable pancreatic cancer (BRPC) is an advanced tumor in contact with the surrounding major vessels, making R0 resection difficult to achieve. Neoadjuvant treatment is expected to provide substantial local control and prolong survival. However, there is no standard treatment. I therefore conducted a strategic literature search from January 2013 to September 2017 and identified 37 clinical studies of pancreatic cancer, including BRPC, to evaluate treatment interventions. Twenty (54%) studies were prospective. Neoadjuvant regimens were as follows: chemotherapy (CT) followed by chemoradiotherapy (CRT) or radiotherapy (RT) (n = 16, 43%), CT alone (n = 11, 30%), CRT alone (n = 9, 24%) and RT alone (n = 1, 3%). Radiotherapy was employed in 70% of the studies. Phase II studies were most frequent (55%), and we were unable to identify a Phase III study. The National Comprehensive Cancer Network’s classifications were most frequently used as criteria for BRPC, although resectability status is not standardized. Radiological central review was used in three of eight multi-institutional studies. Assessing on-going or planned clinical trials for BRPC, administration of oxaliplatin, irinotecan, fluorouracil and leucovorin therapy or albumin-bound paclitaxel plus gemcitabine therapy, and randomized trials that evaluate the significance of CRT or RT combined with CT were identified as important topics for further consideration. Although standardization of classifications and improvement of infrastructure are required, a standard treatment of BRPC will likely be developed, which will improve prognosis in the near future because several important randomized trials are running. pancreas cancer, pancreatic adenocarcinoma, borderline resectable pancreaic cancer, borderline resectable pancreaic adenocarcinoma, neoadjuvant treatment, multidisciplinary treatment, clinical trial Introduction Pancreatic cancer (PC) is one of the leading causes of cancer death (1, 2). Prognosis is dismal, and the 5-year survival rate is ~5% (3). Frequent metastasis prevents patients with PC from receiving a resection, although surgical removal is the sole hope for a cure. When metastasis is not present, a tumor cannot be resected if the major surrounding vessels are highly involved (4,5). Approximately 10–20% of patients present with surgically resectable disease (1,3,6). Borderline resectable pancreatic cancer (BRPC) exhibits a certain, but not high level of contact, with major surrounding vessels (7). The resectability of BRPC is intermediate between resectable PC and unresectable locally advanced PC. BRPC is frequently associated with positive surgical margins and poor prognosis after resection, even if the tumor is resected (8). Although BRPC occurs in ~5–10% of a localized cohort (8), BRPC attracts increased attention and its treatment strategy is a subject of controversy among oncologists during the last decade. One reason is that BRPC is categorized according to its surgical resectability and can be diagnosed preoperatively using radiological findings. Categorization by resectability is sometimes more clinically appropriate compared with TNM staging, particularly making a treatment decision. The emergence of BRPC enables radiological categorization, although this was impossible when resectability was classified as only ‘resectable’ or ‘unresectable.’ Further, BRPC can preoperatively identify a high-risk group of patients with postoperative local and systemic failure. Identification of this group can facilitate developing a multidisciplinary for managing this high-risk group. Actually, clinical studies of multidisciplinary treatment for BRPC are increasing. The information presented in this review leads me to conclude that within the next decade, more efficient treatment of BRPC is likely to be developed, which will help increase its cure rate. In this review, I first consider the definitions of BRPC that are ‘a matter of debate’ and then describe the current challenges presented by BRPC and future directions for improved management of this deadly disease. I place particular emphasis on the development of treatment and the design of clinical trials. For this purpose, I conducted a strategic literature search to identify relevant clinical studies on the evaluation of treatment interventions for BRPC. I used the PubMed and the Web of Science resource’s advanced search option and the keywords ‘borderline resectable pancreatic cancer’ ‘borderline resectable pancreas cancer’ and ‘borderline resectable pancreatic adenocarcinoma’to identify 215 papers published from January 2013 to September 2017. I identified 37 clinical studies of pancreatic cancer, including BRPC, which focused on the evaluation of treatment interventions. I summarize the findings of these studies and their conclusions. Definition of BRPC The concept of BRPC was first proposed by Varadhachary from MD Anderson Cancer Center in 2006 (7), while similar concepts such as ‘marginally resectable pancreatic cancer’ were previously advocated (9). Soon after the initial proposal, BRPC was defined as a category of resectability status in the NCCN guidelines as a tumor frequently associated with a positive surgical margin (5). However, the definition of BRPC is not standardized and remains a subject of debate. For example, the criteria defining the resectability in the NCCN guidelines changed many times (5). Several other definitions were proposed (4,10–13). The guidelines advocated by the AHPBA/SSO/SSAT (14), MD Anderson CC (10) and the Alliance for Clinical Trials in Oncology (11) also have been used widely in clinical studies. The classification (14) was stated as the consensus of the conference on Resectable and Borderline Resectable Pancreatic Cancer, which was convened by the American Hepato-Pancreato-Biliary Association, the Society of Surgical Oncology and the Society for Surgery of the Alimentary Tract (AHPBA/SSO/SSAT). The MD Anderson Cancer Center classification (10) was the first systematic classification of resectability status and served as the reference of the initial classification of the National Comprehensive Cancer Network (NCCN) guidelines. However, the latest criteria of the NCCN guidelines differ from those of MD Anderson Cancer Center classification in many aspects subsequent to multiple revisions. The Alliance Trial classification (11) comprises criteria developed for multi-institutional trials for borderline resectable cancer. The classification was designed according to objective and simple criteria, to avoid misunderstandings caused by subjective evaluations. Further, the Alliance Trial classification is firmly committed to the circumferential tumor–vessel interface. Recently, a classification system for the diagnosis of resectability status was incorporated into the General Rules for the Study of Pancreatic Cancer (7th edition), edited by the Japan Pancreas Society in 2016 (13). This classification is predicted to be used frequently in clinical studies of BRPC, particularly those conducted by Japanese investigators. Differences among these classifications require considerable attention, because they may cause stage-migration that affects prognosis. Classifications of BRPC are summarized in Table 1. Table 1. Classifications of borderline resectable pancreatic cancer   CA  CHA  SMA  PV/SMV  NCCN 2017 (5)  (Head cancer) No contact with CA(Body/Tail cancer) Contact with CA of ≤180° Contact with CA of >180° without aorta or GDA involvement(Permitting modified Appleby procedure)  (Head cancer) Contact with CHA without extension to CA or hepatic artery bifurcation  Contact with SMA of ≤180°(without contact with the first jejunal branch)  Contact with PV/SMV of >180° Contact with PV/SMV of ≤180° with contour irregularity or thrombosis(without contact with the most proximal jejunal branch)  AHPBA/SSO/SSAT (14)  No contact with CA  Abutment or short segment encasement with CHA with GDA encasement (without extension to CA)  Abutment on SMA of ≤180°  Abutment on PV/ SMV with or without reconstructible impingement, narrowing, or occlusion  MD Anderson Cancer Center (10)  Abutment on CA of ≤180°  Abutment or short segment encasement with CHA with GDA encasement  Abutment on SMA of ≤180°  Occlusion of PV/SMV  Alliance Trial (11)  Interface with CA < 180°  Any reconstructible interface with CHA  Interface with SMA < 180°  Interface with PV/ SMV ≥180°  Japan Pancreas Society (13)  Contact with CA < 180° without deformity or narrowing  Any contact with CHA without contact with CA or proper hepatic artery  Contact with SMA < 180° without deformity or narrowing  Contact, encasement ≥180° with PV/SMV or occlusion of PV/SMV(without caudal extensions over the level of inferior end of duodenum)    CA  CHA  SMA  PV/SMV  NCCN 2017 (5)  (Head cancer) No contact with CA(Body/Tail cancer) Contact with CA of ≤180° Contact with CA of >180° without aorta or GDA involvement(Permitting modified Appleby procedure)  (Head cancer) Contact with CHA without extension to CA or hepatic artery bifurcation  Contact with SMA of ≤180°(without contact with the first jejunal branch)  Contact with PV/SMV of >180° Contact with PV/SMV of ≤180° with contour irregularity or thrombosis(without contact with the most proximal jejunal branch)  AHPBA/SSO/SSAT (14)  No contact with CA  Abutment or short segment encasement with CHA with GDA encasement (without extension to CA)  Abutment on SMA of ≤180°  Abutment on PV/ SMV with or without reconstructible impingement, narrowing, or occlusion  MD Anderson Cancer Center (10)  Abutment on CA of ≤180°  Abutment or short segment encasement with CHA with GDA encasement  Abutment on SMA of ≤180°  Occlusion of PV/SMV  Alliance Trial (11)  Interface with CA < 180°  Any reconstructible interface with CHA  Interface with SMA < 180°  Interface with PV/ SMV ≥180°  Japan Pancreas Society (13)  Contact with CA < 180° without deformity or narrowing  Any contact with CHA without contact with CA or proper hepatic artery  Contact with SMA < 180° without deformity or narrowing  Contact, encasement ≥180° with PV/SMV or occlusion of PV/SMV(without caudal extensions over the level of inferior end of duodenum)  CA, celiac axis; CHA, common hepatic artery; SMA, superior mesenteric artery; PV, portal vein; SMV, superior mesenteric vein; GDA, gastroduodenal artery. Venous definition is a controversial component of BRPC and represents a major issue. The BRPC criteria relating to portal and/or superior mesenteric vein (PV/SMV) differ among the aforementioned five classifications listed in Table 1. Concomitant resection of the PV/SMV associated with a pancreatic tumor followed by reconstruction is feasible and a selectable option for a high-volume pancreatic cancer treatment center (15,16). Further, the venous criteria of BRPC differ according to the evaluation of risk related to PV/SMV invasion, that is, how much the contact with the PV affects a patients’ prognosis. In the AHPBA/SSO/SSA classification, any abutment on the PV/SMV, with or without impingement, narrowing, or occlusion is considered BRPC. In contrast, in the MD Anderson CC classification, only cases with occlusion are considered as BRPC as it relates to the PV/SMV. The number, tumor staging or prognosis of eligible patients, is presumably much different whether the AHPBA/SSO/SSA or MD Anderson CC classification is applied to diagnosis resectability. The classifications of the NCCN, Alliance Trial, and Japanese Pancreas Society recommend moderation, and tumor contact with the PV/SMV > 180° is the criterion for BRPC, although the details differ among them. For example, the NCCN guidelines include contact with the PV/SMV ≤180° with contour irregularity or thrombosis, according to the criteria of BRPC. In contrast, in the Alliance Trial guidelines, only the degree of circumferential tumor–vessel interface is considered important to avoid bias introduced by subjective evaluations used in defining the criteria. Further, the caudal limit of tumor extension along the SMV as a criterion for BRPC differs between the classifications of the NCCN and those of the JPS. In the NCCN, the caudal limit is above the most proximal jejunal branch and above the level of the inferior end of duodenum in the JPS. The difference in the distance of tumor contact with the PV/SMV according to the two different criteria may represent several centimeters as cephalocaudal extension in certain cases. These difference may affect the prognosis of BRPC, because the longitudinal distance of PV/SMV invasion is a prognostic factor of resection for pancreatic cancer (17). Criteria relating to the celiac axis (CA) are another important topic. Thus, the NCCN, MD Anderson CC, Alliance Trial, and JPS define contact with the CA < 180° as borderline resectability, whereas the AHPBA/SSO/SSA consensus does not accept any tumor contact with the CA as BRPC. Further, the 2015 NCCN guidelines provide another criterion of BRPC as follows: Contact with the CA > 180° without involvement of the aorta or gastroduodenal artery, permitting the modified Appleby procedure, is included as a criterion of BRPC. However, some members prefer inclusion of this criterion in the unresectable category. Accordingly, this criterion may be extended to more advanced disease, taking advantage of the less common surgical procedure to remove the pancreatic tumor along with the corresponding artery using the inherent collateral vessel (18). Patients eligible according to the newly proposed criteria may have a worse prognosis than those who are eligible according to the other criteria of BRPC. Therefore, detailed consideration is required to decide whether a tumor consistent with the criteria should be deemed BRPC or unresectable PC. Clearly, the outcomes of treatment intervention change when eligibility changes. Nevertheless, the criteria of resectability are critically important. Therefore, the definitions of BRPC should be stated clearly and precisely in the protocol, and we should focus on the differences among criteria for BRPC when comparing outcomes between multiple studies. Neoadjuvant treatment of BRPC BRPC contacts surrounding important vessels, therefore upfront resection is frequently associated with margin-positive resection. Microscopic margin-positive resection is one of the strongest factors of poor prognosis associated with pancreatic cancer (15,19–21), even subsequent to the development of effective adjuvant therapy (22). Consequently, when the tumor is treated with upfront resection and subsequent adjuvant chemotherapy, frequent local or systemic failure and worse prognosis are expected for BRPC compared with a resectable pancreatic cancer. Neoadjuvant therapy may increase the possibility of R0 resection and eradicate systemic micrometastasis and is therefore considered a reasonable approach for treating BRPC. The meta-analysis identified 10 studies reporting that when neoadjuvant treatment of BRPC is administered, 49% of 182 patients achieve R0 resections, and their 2-year survival rate is 41% (23). Neoadjuvant treatment may therefore increase the possibility of R0 resection, leading to longer survival. The types of neoadjuvant treatments for BRPC are presented in Table 2. Neoadjuvant treatment combined with radiotherapy is the most frequently used to treat BRPC. Several studies report the safety and efficacy of neoadjuvant chemotherapy followed by radiation (24–30). The retrospective study of Katz et al. found that neoadjuvant GEM-based combination chemotherapy followed by chemoradiation enables margin-negative resection in 37% of 84 patients with anatomical BRPC (median survival after resection = 40 months), which was diagnosed according to the MD Anderson CC classification (10). In another retrospective study of neoadjuvant GTX followed by SBRT for BRPC (31), an R0 resection rate of 54% (57/106) and median survival time = 16.4 months were achieved with adequate feasibility. Moreover, in a Phase II study of non-metastatic pancreatic cancer, the feasibility and effectiveness of systemic GEM and subsequent full-dose GEM with concurrent radiotherapy was reported for 3/9 R0 resections (32). The treatment regimen was completed in 33 of 39 enrolled patients. Grade 3 to 4 non-hematologic toxicities related to treatment was observed in only 25.6%. The 1-year survival rate was 76% for the nine borderline-resectable patients. Table 2. BRPC clinical trials conducted between 2013 and 2017 Author  Year  Study design  Institution  Radiological central review  Resectability criteria  Stage of object  Number of BRPC points  Neoadjuvant treatment  R0 resection rate of BRPC (including non-resected cases)  MST of BRPC pts (months)  Motoi (66)  2013  PII  Multi  No  Other  R/BR  16  CT (GEM + S-1)  –  –  Kim (33)  2013  PII  Single  –  NCCN  R/BR/URLA  39  CRT (concurrent GEMOX)  –  18.4  Takahashi (34)  2013  PII  Single  –  Other (modified MD Anderson)  R/BR  80  CT (GEM) followed by CRT (concurrent GEM) and subsequent liver perfusion chemotherapy  53%  –  Takeda (36)  2014  PI/II  Multi  No  Other  BR  35  CRT (concurrent GEM)  74%  –  Esnaola (25)  2014  PII  Single  –  Other  BR/UR  13  CT (GEMOX + cetuximab) followed by CRT (concurrent capecitabine)  69%  24.1  Sahora (67)  2014  PII  Single  –  Other  BR/URLA  11  CT (GEM + bevacizumab)  –  –  Jensen (37)  2014  PII  Single  –  Other  BR/URLA  23  CRT (concurrent FP+INFα)  26%  11.5  Holyoake (68)  2016  PI  Multi  No  NCCN  BR  24  Margin intensive SBRT  –  –  Shaib (53)  2016  PI  Single  –  Alliance Trial  BR  13  CT (mFOLFIRINOX) followed by SBRT  62%  11.0  Nywening (69)  2016  PIb  Single  –  AHPBA/SSO/SSAT  BR/URLA  47  CT (FOLFIRINOX + PF-04 136 309)  –  –  Reni (70)  2016  PIb  Single  –  NCCN  BR/URLA  6  CT (GEM + nab-PTX+capecitabine+CDDP)  –  14.5  Katz (51)  2016  PII  Multi  Yes  Alliance Trial  BR  23  CT (mFOLFIRINOX) followed by CRT (concurrent capecitabine)  61%  21.7  Versteijne (27)  2016  ran PII  Multi  No  Other  R/BR  –  CT (GEM) followed by CRT (concurrent GEM) and subsequent CT (GEM) vs. adjuvant CT (GEM)  –  –  Kondo (71)  2017  PI  Multi  No  NCCN  BR/URLA  13  CT (GEM + nab-PTX + S-1)  –  –  Okada (72)  2017  PI  Single  –  NCCN  BR  10  CT (GEM + nab-PTX)  70%  –  Nagakawa (73)  2017  PII  Single  –  Original  BR(Artery)  27  IMRT (concurrent GEM + S-1)  67%  22.4  Okano (38)  2017  PII  Single  –  NCCN  R/BR  24  CRT (concurrent S-1)  –  –  Fiore (28)  2017  PII  Single  –  NCCN  BR/URLA  7  CT (GEMOX) followed by CRT (concurrent GEM)  56%  21.5  Takahashi (39)  2017  PII  Multi  Yes  Other (modified NCCN)  BR  57  CRT (concurrent S-1)  63%  –  Katz (56)  2017  Ran PII  Multi  Yes  Alliance Trial  BR(head)  124  CT (mFOLFIRINOX) with or without SBRT  –  –  Author  Year  Study design  Institution  Radiological central review  Resectability criteria  Stage of object  Number of BRPC points  Neoadjuvant treatment  R0 resection rate of BRPC (including non-resected cases)  MST of BRPC pts (months)  Motoi (66)  2013  PII  Multi  No  Other  R/BR  16  CT (GEM + S-1)  –  –  Kim (33)  2013  PII  Single  –  NCCN  R/BR/URLA  39  CRT (concurrent GEMOX)  –  18.4  Takahashi (34)  2013  PII  Single  –  Other (modified MD Anderson)  R/BR  80  CT (GEM) followed by CRT (concurrent GEM) and subsequent liver perfusion chemotherapy  53%  –  Takeda (36)  2014  PI/II  Multi  No  Other  BR  35  CRT (concurrent GEM)  74%  –  Esnaola (25)  2014  PII  Single  –  Other  BR/UR  13  CT (GEMOX + cetuximab) followed by CRT (concurrent capecitabine)  69%  24.1  Sahora (67)  2014  PII  Single  –  Other  BR/URLA  11  CT (GEM + bevacizumab)  –  –  Jensen (37)  2014  PII  Single  –  Other  BR/URLA  23  CRT (concurrent FP+INFα)  26%  11.5  Holyoake (68)  2016  PI  Multi  No  NCCN  BR  24  Margin intensive SBRT  –  –  Shaib (53)  2016  PI  Single  –  Alliance Trial  BR  13  CT (mFOLFIRINOX) followed by SBRT  62%  11.0  Nywening (69)  2016  PIb  Single  –  AHPBA/SSO/SSAT  BR/URLA  47  CT (FOLFIRINOX + PF-04 136 309)  –  –  Reni (70)  2016  PIb  Single  –  NCCN  BR/URLA  6  CT (GEM + nab-PTX+capecitabine+CDDP)  –  14.5  Katz (51)  2016  PII  Multi  Yes  Alliance Trial  BR  23  CT (mFOLFIRINOX) followed by CRT (concurrent capecitabine)  61%  21.7  Versteijne (27)  2016  ran PII  Multi  No  Other  R/BR  –  CT (GEM) followed by CRT (concurrent GEM) and subsequent CT (GEM) vs. adjuvant CT (GEM)  –  –  Kondo (71)  2017  PI  Multi  No  NCCN  BR/URLA  13  CT (GEM + nab-PTX + S-1)  –  –  Okada (72)  2017  PI  Single  –  NCCN  BR  10  CT (GEM + nab-PTX)  70%  –  Nagakawa (73)  2017  PII  Single  –  Original  BR(Artery)  27  IMRT (concurrent GEM + S-1)  67%  22.4  Okano (38)  2017  PII  Single  –  NCCN  R/BR  24  CRT (concurrent S-1)  –  –  Fiore (28)  2017  PII  Single  –  NCCN  BR/URLA  7  CT (GEMOX) followed by CRT (concurrent GEM)  56%  21.5  Takahashi (39)  2017  PII  Multi  Yes  Other (modified NCCN)  BR  57  CRT (concurrent S-1)  63%  –  Katz (56)  2017  Ran PII  Multi  Yes  Alliance Trial  BR(head)  124  CT (mFOLFIRINOX) with or without SBRT  –  –  BRPC, borderline resectable pancreatic cancer; PI, Phase I; PII, Phase II; ran PII, randomized Phase II; Multi, multicenter; Single, single-center; R, resectable pancreatic cancer; BR, BRPC; URLA, unresectable locally advanced pancreatic cancer; CT, chemotherapy; CRT, chemoradiotherapy; SBRT, stereotactic body radiotherapy; IMRT, Intensity Modulated Radiation Therapy; GEM, gemcitabine; INF, interferon; mFOLFIRINOX, modified FOLFIRINOX; CDDP, cisplatin; nab-PTX, albumin-bound paclitaxel; MST, median survival time. In contrast, neoadjuvant chemoradiation without systemic induction chemotherapy is used to treat BRPC (33–39). Massucco et al. report the outcome of pancreatic resections after GEM with concurrent radiation for locally advanced pancreatic cancer, including BRPC. Gemcitabine of 50 mg/m2 was more feasible than that of 100 mg/m2 being used concurrently with radiation. Of the 18 borderline-resectable patients, a 28% partial response and a 39% R0 resection rate is achieved after neoadjuvant CRT (40). The efficacy and safety of the neoadjuvant capecitabine and concurrent radiation were evaluated in a Phase II study (41). Capecitabine-based chemoradiation is well tolerated and attributed to 12/40 R0 resections, according to the MD Anderson CC classification. Further, the authors report a favorable prognosis of the resected BRPC after CRT, which is comparable with that of resectable pancreatic cancer. Evidence indicates that a combination chemotherapy regimen consisting of oxaliplatin, irinotecan, fluorouracil and leucovorin (FOLFIRINOX) serves as neoadjuvant treatment of BRPC (42), because it exhibits excellent antitumor activity and is now considered standard treatment of patients with metastatic pancreatic cancer (43). In retrospective studies, FOLFIRINOX was evaluated as preoperative therapy for BRPC, anticipating tumor shrinkage and eradication of micrometastasis (44–46). Hosein et al. report the experience of FOLFIRINOX for unresectable or borderline resectable PC. Three (17%) of 18 patients developed febrile neutropenia despite the use of prophylactic filgrastim, however, the regimen’s toxicity was generally manageable. R0 resection was achieved in three (75%) out of four borderline-resectable patients (47). Systemic chemotherapies such as FOLFILINOX or albumin-bound paclitaxel (nab-paclitaxel) plus gemcitabine therapy (GEM + nab-PTX) achieve high-antitumor activity (43,48) and is likely more easily available compared with CRT. The objective response rates of FOLFIRINOX (43) and GEM + nab-PTX (48,49) for metastatic pancreatic cancer were 31.6% and 23–59%, whereas that of gemcitabine which had been the former standard of care was 7–9% (43,48). Systemic chemotherapy alone may provide an alternative for radiotherapy as neoadjuvant treatment of BRPC when the efficacy of treatment, including local effects, is confirmed as not inferior to other radiotherapy treatments. In contrast, more intensive treatment using neoadjuvant-induction chemotherapy using FOIFILINOX or GEM + nab-PTX followed by RT represents another direction for developing treatments for BRPC (50–55). For example, the prospective cohort study conducted by Christians et al. evaluated neoadjuvant FOLFIRINOX and subsequent capecitabine-based chemoradiotherapy for BRPC (50). They concluded that FOLFIRINOX followed by chemoradiation was feasible as neoadjuvant therapy for BRPC and achieved a favorable resection rate = 67% in 18 patients. Grade 3/4 toxicity rate associated with FOLFIRINOX was 75%, and nausea/vomiting was most frequently observed (35.7%). There were no perioperative deaths nor reoperations. The Phase II study conducted by the Alliance for Clinical Trials in Oncology Trial A021101, which is notable for its approach for optimizing study design for BRPC, evaluated the feasibility of preoperatively modified FOLFIRINOX followed by capecitabine-based chemoradiation in patients with BRPC (51). This trial achieved a comparatively high efficacy (R0 resection rate = 64%) in the first intergroup feasibility study of BRPC. The modified FOLFIRINOX protocol, followed by capecitabine-based chemoradiation, was tolerable; however, 64% of the patients experienced ≥Grade-3 adverse events during preoperative treatment. During the preparation of this review, several prospective studies for BRPC were underway (Trial identifires: ClinicalTrials.gov; ISRCTN registry; EORTC clinical trials database.). Most of these studies are Phase I or II. Concurrently, several randomized Phase II or Phase II/III studies comparing different treatments were started to analyze a BRPC cohort. A Phase II study conducted at the University of Pittsburg (NCT02241551) compared mFOLFIRINOX and GEM + nab-PTX as induction chemotherapy before SBRT in the context of developing more intensive treatment using systemic chemotherapy and radiotherapy. In contrast, a few randomized Phase II studies aim to determine the significance of radiotherapy combined with systemic chemotherapy for treating BRPC. Clinical trials in the USA (A021501, NCT02839343) and Europe (PANDAS-PRODIGE44, NCT02676349) are comparing mFOLFIRINOX with or without subsequent radiation as neoadjuvant therapy. The Alliance for Clinical Trials in Oncology uses hypofractioned radiation (56). In contrast, the PANDAS-PRODIGE trial employs capecitabine and concurrent radiation. In comparison, a Phase II/III study (UMIN000026858) compares chemoradiotherapy or chemotherapy alone as neoadjuvant therapy for BRPC. There may be a considerable population not fit for the treatment using both systemic chemotherapy and radiotherapy, considering its intensity. Therefore, the thesis has importance, particularly in an aging population. The results of these studies will set a new direction for the treatment of BRPC in the near future. Phase III study is substantially essential for establishing a standard treatment for BRPC. A randomized Phase III trial comparing a most promising neoadjuvant treatment with upfront surgery seems to be reasonable because a standard treatment using neoadjuvant treatment has not been demonstrate yet. While at the same time, difficult patient-registration is anticipated in Phase III study using upfront surgery as the standard therapy considering recommendation by guidelines of neoadjuvant treatment or physicians’ preference. Then, a Phase III trial using two considered standard treatments may be one of the realistic options in BRPC. In that case, considered treatments must be chosen in view of risk/benefit balances among the most promising neoadjuvant treatments. Either way, feasibility and consensus about the trial concept will be key to successful Phase III trial. Development of a study design for BRPC Delays in standardizing the treatment of BRPC partly result from lack of standardization of clinical trial designs caused by several obstacles. First, BRPC accounts for 5–10% of nonmetastasized PC (8,10). Therefore, the feasibility of conducting a clinical trial requires a global or intergroup study or relaxing the statistical parameters for predicting a sufficient sample size. Second, the definition of BRPC differs among guidelines. In particular, the definition of tumor–portal vein contact differs so much that it could bias the results of the trial. If the definitions of BRPC are not standardized, this should be clearly stated in the protocol to ensure that the results of trials can be compared. Further, the interpretation of multidetector CT (MDCT) findings varies among institutions. Accordingly, all MDCTs used for registration should ideally be diagnosed through central diagnosis. Third, the indications for surgical resection after neoadjuvant treatment are not standardized. The tumor–vessel interactions of BRPC rarely improves to those of resectable PC after several months of preoperative treatment (12,46). Most BRPC remains borderline resectable. Moreover, some cases of BRPC appear to be unresectable PC after neoadjuvant therapy, and radiological resectability status does not necessarily correspond with the possibility of R0 resection after neoadjuvant treatment. Therefore, indications for surgical resection after neoadjuvant treatment should be stated in a protocol. However, the details of surgical indications are rarely stated in the studies analyzed here. The heterogeneity of clinical trial designs for BRPC is reported by Katz et al. Katz et al. reviewed 23 studies published from 2001 to 2012, which include 35% prospective studies (11). For example, unambiguous inconsistency was observed in the stages studied, staging classifications, indications for surgery, and the endpoint defined to evaluate treatment. They advocated the necessity of standardizing clinical trial design in all future studies of BRPC. Our present study found that 54% of the trials are prospective, indicating an encouraging trend that promises to achieve a standardized design of BRPC clinical trials. In this review, 37 studies for pancreatic cancer, including BRPC, were analyzed. Of the 37 studies, 20 prospective studies are listed in Table 2. The number of patients with BRPC was <30 in 13 (65%) of the 20 trials, and >50 in three studies (Fig. 1). These numbers likely attest to the infrequent occurrence of BRPC and to the inability to identify a Phase III study (Fig. 2). Figure 1. View largeDownload slide Sample sizes of the 20 clinical trials for BRPC reported between 2013 and 2017. The sample sizes of 13 (65%) of the 20 trials were <30 and >50 in three. Figure 1. View largeDownload slide Sample sizes of the 20 clinical trials for BRPC reported between 2013 and 2017. The sample sizes of 13 (65%) of the 20 trials were <30 and >50 in three. Figure 2. View largeDownload slide Study phases of the 20 clinical trials for BRPC reported between 2013 and 2017. Approximately 50% of the 20 trials were Phase II, followed by Phase I. There were two randomized Phase II studies, and a Phase III study was not identified by our strategic literature search. PI, Phase I; PII, Phase II, random PII, randomized Phase II; PIII, Phase III. Figure 2. View largeDownload slide Study phases of the 20 clinical trials for BRPC reported between 2013 and 2017. Approximately 50% of the 20 trials were Phase II, followed by Phase I. There were two randomized Phase II studies, and a Phase III study was not identified by our strategic literature search. PI, Phase I; PII, Phase II, random PII, randomized Phase II; PIII, Phase III. Trials targeting BRPC alone are increasing, but the number remains small, partly because of its rarity. Many studies (60%) target BRPC as well as resectable or unresectable localized pancreatic cancer. The populations are as follows: patients with resectable or borderline resectable PC, patients with borderline resectable or unresectable locally advanced PC, and patients with localized PC independent of resectability (Fig. 3). The target of the study could be changed by treatment strategy; however, clinical trials of only BRPC are urgently required to establish a standard treatment. Figure 3. View largeDownload slide Resectability stage object of the 20 clinical trials for BRPC reported between 2013 and 2017. Many studies (60%) targeted BRPC as well as resectable or unresectable localized pancreatic cancer. Figure 3. View largeDownload slide Resectability stage object of the 20 clinical trials for BRPC reported between 2013 and 2017. Many studies (60%) targeted BRPC as well as resectable or unresectable localized pancreatic cancer. When the resectability criteria used in all 37 studies were examined, the NCCN classification was used most frequently, followed by the AHPBA/SSO/SSAT classification (Fig. 4a). In 20 prospective clinical trials, the Alliance Trial classification was the second most frequent criteria, while the Alliance Trial criteria were formulated to promote global standardization of the resectability classifications (Fig. 4b). In contrast, seven of the clinical trials for BRPC applied the original classifications for diagnosing surgical resectability. Standardization of resectability criteria is a pressing issue for managing BRPC. Figure 4. View largeDownload slide (a) Resectability criteria used in 37 studies that examined neoadjuvant treatment of BRPC. The NCCN classification criteria were used most frequently, followed by the AHPBA/SSO/SSAT classification. (b) Resectability criteria used in 20 prospective trials of BRPC. The NCCN classification was used most frequently. In contrast to the results of the 37 studies, the Alliance Trial classification criteria were the second most frequently used in the prospective clinical trials. NCCN, National Comprehensive Cancer Network; AHPBA, American Hepato-Pancreato-Biliary Association; SS0, Society of Surgical Oncology; SSAT; Society for Surgery of the Alimentary Tract. Figure 4. View largeDownload slide (a) Resectability criteria used in 37 studies that examined neoadjuvant treatment of BRPC. The NCCN classification criteria were used most frequently, followed by the AHPBA/SSO/SSAT classification. (b) Resectability criteria used in 20 prospective trials of BRPC. The NCCN classification was used most frequently. In contrast to the results of the 37 studies, the Alliance Trial classification criteria were the second most frequently used in the prospective clinical trials. NCCN, National Comprehensive Cancer Network; AHPBA, American Hepato-Pancreato-Biliary Association; SS0, Society of Surgical Oncology; SSAT; Society for Surgery of the Alimentary Tract. Neoadjuvant CT followed by RT or CRT was most frequently administered to patients with BRPC (Fig. 5). Radiation was used in 70% of the 37 studies, which indicates that radiotherapy is considered to contribute to the treatment for BRPC subject to local failure. Figure 5. View largeDownload slide Neoadjuvant treatment used in 37 studies, which examined neoadjuvant treatment of BRPC. Neoadjuvant CT followed by RT or CRT was most frequently applied to treat BRPC. Radiation was used in 70% of the 37 studies. CT, chemotherapy; RT, radiotherapy; CRT, chemoradiotherapy. Figure 5. View largeDownload slide Neoadjuvant treatment used in 37 studies, which examined neoadjuvant treatment of BRPC. Neoadjuvant CT followed by RT or CRT was most frequently applied to treat BRPC. Radiation was used in 70% of the 37 studies. CT, chemotherapy; RT, radiotherapy; CRT, chemoradiotherapy. A review of 37 studies published from 2013 to 2017 reveals that multi-institutional studies increased. Conducting multi-institutional study is essential for Phase III studies of such a rare disease. Moreover, multi-institutional studies for BRPC require additional infrastructure such as centralized radiological and pathological reviews. However, few multi-institutional studies implemented a centralized radiological review. In summary, the number of clinical trials for BRPC has increased from 23 in the former 12 years to 37 in the recent 5 years, but few are randomized trials. However, a few clinical trials were conducted that were optimized for BRPC. Standardization of classifications and improvement of infrastructure are required for further promotion of clinical trials for BRPC, which will accelerate the development of a standardized treatment for BRPC. Surgical resection to treat BRPC Surgery for BRPC can be performed with techniques developed over the years; however, special care is required for surgical indications such as the approach to the corresponding artery and concomitant vessel resection. After neoadjuvant therapy, radiological tumor morphology does not reflect antitumor effects. The RECIST tumor response does not match the pathological response after neoadjuvant treatment (12,46), partly because radiological morphology can be affected by treatment effects such as edema or inflammation. Morphological changes usually follow soon after treatment, particularly after radiotherapy. Further, resectability status according to the classification after neoadjuvant treatment does not represent actual resectability (46). Even when the tumor does not seem to respond to the preceding treatment, or is not down-staged after treatment, R0 resection may be achieved. Therefore, unless progressive disease, defined according to the RECIST rules, is observed, it is preferable to perform laparotomy. The trend of the serum CA19-9 value after neoadjuvant treatment may help patients to decide to undergo laparotomy, particularly those with BRPC that does not respond to radiotherapy (4,57,58). The surgeon must first determine whether the tumor is resectable, because the tumor contacts the surrounding major artery or vein. Resectability should be judged before the procedure passes the point of no return. In particular, the retroperitoneal SMA margin likely results in a higher rate of microscopic positive surgical margins because of its close proximity to the head of the pancreas, while a positive SMA margin frequently causes local failure. Therefore, an artery-first approach for SMA is now frequently used to instantaneously determine resectability and to acquire a higher R0-resection rate for pancreaticoduodenectomy (59,60). Moreover, several clinical studies validate the effect of the ‘artery-first approach’ in pancreaticoduodenectomy for pancreatic cancer (NCT03224832, NCT02803814, NCT01332773). In BRPC, resection of the PV/SMV is often required and is expected when required for R0 resection. Venous criteria of resectability guidelines presuppose the feasibility of safe and complete resection and reconstruction (61). A large meta-analysis shows that addition of venous resection does not increase morbidity, mortality or decrease 5-year overall survival comparing pancreatectomy without venous resection (15,62). In contrast, increased morbidity and mortality occur in concomitant arterial resection with pancreatectomy, although the prognosis of patients after the combined arterial and pancreatic resections is superior compared with those who did not undergo pancreatic resection (63,64). Therefore, concomitant arterial resection should be limited to highly selected patients and performed in specialized centers. BRPC located in the pancreas body often contacts the celiac axis or common hepatic artery. Distal pancreatectomy with celiac axis resection (DP-CAR) or a modified Appleby resection can remove the tumor, the corresponding celiac axis, and the common hepatic artery as en block without reconstruction using the collateral artery of the pancreatic arcade (18,65). The surgeries are uncommon but sometimes performed in specialized centers for treating pancreatic cancer. The modified Appleby procedures or DP-CAR may lead to improved safety after en block tumor and artery resections and facilitate resections of BRPC or unresectable PC. Therefore, the feasibility and effects of the aforementioned surgeries should be evaluated in clinical studies of BRPC. Conclusions BRPC is one of the targets of multidisciplinary approaches using neoadjuvant treatment of pancreatic cancer, because it is frequently associated with locoregional or systemic failure, even if the tumor is resected. Therefore, a multidisciplinary team including a surgeon, oncologist, radiation oncologist and radiologist is critically important for the optimum treatment for BRPC. Presently, neoadjuvant chemotherapy followed by chemoradiation is the major treatment strategy. Moreover, a number of clinical trials of BRPC are in progress. Although standardization of classifications and improvement of infrastructure are required, efficient treatment of BRPC likely will be developed in the near future and will help increase the cure rate of this deadly disease. Funding This work is supported by the Practical Research for Innovative Cancer Control from Japan Agency for Medical Research and Development, AMED (15Ack0106154h0001). Conflict of interest statement None declared. 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How to treat borderline resectable pancreatic cancer: current challenges and future directions

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Abstract

Abstract Borderline resectable pancreatic cancer (BRPC) is an advanced tumor in contact with the surrounding major vessels, making R0 resection difficult to achieve. Neoadjuvant treatment is expected to provide substantial local control and prolong survival. However, there is no standard treatment. I therefore conducted a strategic literature search from January 2013 to September 2017 and identified 37 clinical studies of pancreatic cancer, including BRPC, to evaluate treatment interventions. Twenty (54%) studies were prospective. Neoadjuvant regimens were as follows: chemotherapy (CT) followed by chemoradiotherapy (CRT) or radiotherapy (RT) (n = 16, 43%), CT alone (n = 11, 30%), CRT alone (n = 9, 24%) and RT alone (n = 1, 3%). Radiotherapy was employed in 70% of the studies. Phase II studies were most frequent (55%), and we were unable to identify a Phase III study. The National Comprehensive Cancer Network’s classifications were most frequently used as criteria for BRPC, although resectability status is not standardized. Radiological central review was used in three of eight multi-institutional studies. Assessing on-going or planned clinical trials for BRPC, administration of oxaliplatin, irinotecan, fluorouracil and leucovorin therapy or albumin-bound paclitaxel plus gemcitabine therapy, and randomized trials that evaluate the significance of CRT or RT combined with CT were identified as important topics for further consideration. Although standardization of classifications and improvement of infrastructure are required, a standard treatment of BRPC will likely be developed, which will improve prognosis in the near future because several important randomized trials are running. pancreas cancer, pancreatic adenocarcinoma, borderline resectable pancreaic cancer, borderline resectable pancreaic adenocarcinoma, neoadjuvant treatment, multidisciplinary treatment, clinical trial Introduction Pancreatic cancer (PC) is one of the leading causes of cancer death (1, 2). Prognosis is dismal, and the 5-year survival rate is ~5% (3). Frequent metastasis prevents patients with PC from receiving a resection, although surgical removal is the sole hope for a cure. When metastasis is not present, a tumor cannot be resected if the major surrounding vessels are highly involved (4,5). Approximately 10–20% of patients present with surgically resectable disease (1,3,6). Borderline resectable pancreatic cancer (BRPC) exhibits a certain, but not high level of contact, with major surrounding vessels (7). The resectability of BRPC is intermediate between resectable PC and unresectable locally advanced PC. BRPC is frequently associated with positive surgical margins and poor prognosis after resection, even if the tumor is resected (8). Although BRPC occurs in ~5–10% of a localized cohort (8), BRPC attracts increased attention and its treatment strategy is a subject of controversy among oncologists during the last decade. One reason is that BRPC is categorized according to its surgical resectability and can be diagnosed preoperatively using radiological findings. Categorization by resectability is sometimes more clinically appropriate compared with TNM staging, particularly making a treatment decision. The emergence of BRPC enables radiological categorization, although this was impossible when resectability was classified as only ‘resectable’ or ‘unresectable.’ Further, BRPC can preoperatively identify a high-risk group of patients with postoperative local and systemic failure. Identification of this group can facilitate developing a multidisciplinary for managing this high-risk group. Actually, clinical studies of multidisciplinary treatment for BRPC are increasing. The information presented in this review leads me to conclude that within the next decade, more efficient treatment of BRPC is likely to be developed, which will help increase its cure rate. In this review, I first consider the definitions of BRPC that are ‘a matter of debate’ and then describe the current challenges presented by BRPC and future directions for improved management of this deadly disease. I place particular emphasis on the development of treatment and the design of clinical trials. For this purpose, I conducted a strategic literature search to identify relevant clinical studies on the evaluation of treatment interventions for BRPC. I used the PubMed and the Web of Science resource’s advanced search option and the keywords ‘borderline resectable pancreatic cancer’ ‘borderline resectable pancreas cancer’ and ‘borderline resectable pancreatic adenocarcinoma’to identify 215 papers published from January 2013 to September 2017. I identified 37 clinical studies of pancreatic cancer, including BRPC, which focused on the evaluation of treatment interventions. I summarize the findings of these studies and their conclusions. Definition of BRPC The concept of BRPC was first proposed by Varadhachary from MD Anderson Cancer Center in 2006 (7), while similar concepts such as ‘marginally resectable pancreatic cancer’ were previously advocated (9). Soon after the initial proposal, BRPC was defined as a category of resectability status in the NCCN guidelines as a tumor frequently associated with a positive surgical margin (5). However, the definition of BRPC is not standardized and remains a subject of debate. For example, the criteria defining the resectability in the NCCN guidelines changed many times (5). Several other definitions were proposed (4,10–13). The guidelines advocated by the AHPBA/SSO/SSAT (14), MD Anderson CC (10) and the Alliance for Clinical Trials in Oncology (11) also have been used widely in clinical studies. The classification (14) was stated as the consensus of the conference on Resectable and Borderline Resectable Pancreatic Cancer, which was convened by the American Hepato-Pancreato-Biliary Association, the Society of Surgical Oncology and the Society for Surgery of the Alimentary Tract (AHPBA/SSO/SSAT). The MD Anderson Cancer Center classification (10) was the first systematic classification of resectability status and served as the reference of the initial classification of the National Comprehensive Cancer Network (NCCN) guidelines. However, the latest criteria of the NCCN guidelines differ from those of MD Anderson Cancer Center classification in many aspects subsequent to multiple revisions. The Alliance Trial classification (11) comprises criteria developed for multi-institutional trials for borderline resectable cancer. The classification was designed according to objective and simple criteria, to avoid misunderstandings caused by subjective evaluations. Further, the Alliance Trial classification is firmly committed to the circumferential tumor–vessel interface. Recently, a classification system for the diagnosis of resectability status was incorporated into the General Rules for the Study of Pancreatic Cancer (7th edition), edited by the Japan Pancreas Society in 2016 (13). This classification is predicted to be used frequently in clinical studies of BRPC, particularly those conducted by Japanese investigators. Differences among these classifications require considerable attention, because they may cause stage-migration that affects prognosis. Classifications of BRPC are summarized in Table 1. Table 1. Classifications of borderline resectable pancreatic cancer   CA  CHA  SMA  PV/SMV  NCCN 2017 (5)  (Head cancer) No contact with CA(Body/Tail cancer) Contact with CA of ≤180° Contact with CA of >180° without aorta or GDA involvement(Permitting modified Appleby procedure)  (Head cancer) Contact with CHA without extension to CA or hepatic artery bifurcation  Contact with SMA of ≤180°(without contact with the first jejunal branch)  Contact with PV/SMV of >180° Contact with PV/SMV of ≤180° with contour irregularity or thrombosis(without contact with the most proximal jejunal branch)  AHPBA/SSO/SSAT (14)  No contact with CA  Abutment or short segment encasement with CHA with GDA encasement (without extension to CA)  Abutment on SMA of ≤180°  Abutment on PV/ SMV with or without reconstructible impingement, narrowing, or occlusion  MD Anderson Cancer Center (10)  Abutment on CA of ≤180°  Abutment or short segment encasement with CHA with GDA encasement  Abutment on SMA of ≤180°  Occlusion of PV/SMV  Alliance Trial (11)  Interface with CA < 180°  Any reconstructible interface with CHA  Interface with SMA < 180°  Interface with PV/ SMV ≥180°  Japan Pancreas Society (13)  Contact with CA < 180° without deformity or narrowing  Any contact with CHA without contact with CA or proper hepatic artery  Contact with SMA < 180° without deformity or narrowing  Contact, encasement ≥180° with PV/SMV or occlusion of PV/SMV(without caudal extensions over the level of inferior end of duodenum)    CA  CHA  SMA  PV/SMV  NCCN 2017 (5)  (Head cancer) No contact with CA(Body/Tail cancer) Contact with CA of ≤180° Contact with CA of >180° without aorta or GDA involvement(Permitting modified Appleby procedure)  (Head cancer) Contact with CHA without extension to CA or hepatic artery bifurcation  Contact with SMA of ≤180°(without contact with the first jejunal branch)  Contact with PV/SMV of >180° Contact with PV/SMV of ≤180° with contour irregularity or thrombosis(without contact with the most proximal jejunal branch)  AHPBA/SSO/SSAT (14)  No contact with CA  Abutment or short segment encasement with CHA with GDA encasement (without extension to CA)  Abutment on SMA of ≤180°  Abutment on PV/ SMV with or without reconstructible impingement, narrowing, or occlusion  MD Anderson Cancer Center (10)  Abutment on CA of ≤180°  Abutment or short segment encasement with CHA with GDA encasement  Abutment on SMA of ≤180°  Occlusion of PV/SMV  Alliance Trial (11)  Interface with CA < 180°  Any reconstructible interface with CHA  Interface with SMA < 180°  Interface with PV/ SMV ≥180°  Japan Pancreas Society (13)  Contact with CA < 180° without deformity or narrowing  Any contact with CHA without contact with CA or proper hepatic artery  Contact with SMA < 180° without deformity or narrowing  Contact, encasement ≥180° with PV/SMV or occlusion of PV/SMV(without caudal extensions over the level of inferior end of duodenum)  CA, celiac axis; CHA, common hepatic artery; SMA, superior mesenteric artery; PV, portal vein; SMV, superior mesenteric vein; GDA, gastroduodenal artery. Venous definition is a controversial component of BRPC and represents a major issue. The BRPC criteria relating to portal and/or superior mesenteric vein (PV/SMV) differ among the aforementioned five classifications listed in Table 1. Concomitant resection of the PV/SMV associated with a pancreatic tumor followed by reconstruction is feasible and a selectable option for a high-volume pancreatic cancer treatment center (15,16). Further, the venous criteria of BRPC differ according to the evaluation of risk related to PV/SMV invasion, that is, how much the contact with the PV affects a patients’ prognosis. In the AHPBA/SSO/SSA classification, any abutment on the PV/SMV, with or without impingement, narrowing, or occlusion is considered BRPC. In contrast, in the MD Anderson CC classification, only cases with occlusion are considered as BRPC as it relates to the PV/SMV. The number, tumor staging or prognosis of eligible patients, is presumably much different whether the AHPBA/SSO/SSA or MD Anderson CC classification is applied to diagnosis resectability. The classifications of the NCCN, Alliance Trial, and Japanese Pancreas Society recommend moderation, and tumor contact with the PV/SMV > 180° is the criterion for BRPC, although the details differ among them. For example, the NCCN guidelines include contact with the PV/SMV ≤180° with contour irregularity or thrombosis, according to the criteria of BRPC. In contrast, in the Alliance Trial guidelines, only the degree of circumferential tumor–vessel interface is considered important to avoid bias introduced by subjective evaluations used in defining the criteria. Further, the caudal limit of tumor extension along the SMV as a criterion for BRPC differs between the classifications of the NCCN and those of the JPS. In the NCCN, the caudal limit is above the most proximal jejunal branch and above the level of the inferior end of duodenum in the JPS. The difference in the distance of tumor contact with the PV/SMV according to the two different criteria may represent several centimeters as cephalocaudal extension in certain cases. These difference may affect the prognosis of BRPC, because the longitudinal distance of PV/SMV invasion is a prognostic factor of resection for pancreatic cancer (17). Criteria relating to the celiac axis (CA) are another important topic. Thus, the NCCN, MD Anderson CC, Alliance Trial, and JPS define contact with the CA < 180° as borderline resectability, whereas the AHPBA/SSO/SSA consensus does not accept any tumor contact with the CA as BRPC. Further, the 2015 NCCN guidelines provide another criterion of BRPC as follows: Contact with the CA > 180° without involvement of the aorta or gastroduodenal artery, permitting the modified Appleby procedure, is included as a criterion of BRPC. However, some members prefer inclusion of this criterion in the unresectable category. Accordingly, this criterion may be extended to more advanced disease, taking advantage of the less common surgical procedure to remove the pancreatic tumor along with the corresponding artery using the inherent collateral vessel (18). Patients eligible according to the newly proposed criteria may have a worse prognosis than those who are eligible according to the other criteria of BRPC. Therefore, detailed consideration is required to decide whether a tumor consistent with the criteria should be deemed BRPC or unresectable PC. Clearly, the outcomes of treatment intervention change when eligibility changes. Nevertheless, the criteria of resectability are critically important. Therefore, the definitions of BRPC should be stated clearly and precisely in the protocol, and we should focus on the differences among criteria for BRPC when comparing outcomes between multiple studies. Neoadjuvant treatment of BRPC BRPC contacts surrounding important vessels, therefore upfront resection is frequently associated with margin-positive resection. Microscopic margin-positive resection is one of the strongest factors of poor prognosis associated with pancreatic cancer (15,19–21), even subsequent to the development of effective adjuvant therapy (22). Consequently, when the tumor is treated with upfront resection and subsequent adjuvant chemotherapy, frequent local or systemic failure and worse prognosis are expected for BRPC compared with a resectable pancreatic cancer. Neoadjuvant therapy may increase the possibility of R0 resection and eradicate systemic micrometastasis and is therefore considered a reasonable approach for treating BRPC. The meta-analysis identified 10 studies reporting that when neoadjuvant treatment of BRPC is administered, 49% of 182 patients achieve R0 resections, and their 2-year survival rate is 41% (23). Neoadjuvant treatment may therefore increase the possibility of R0 resection, leading to longer survival. The types of neoadjuvant treatments for BRPC are presented in Table 2. Neoadjuvant treatment combined with radiotherapy is the most frequently used to treat BRPC. Several studies report the safety and efficacy of neoadjuvant chemotherapy followed by radiation (24–30). The retrospective study of Katz et al. found that neoadjuvant GEM-based combination chemotherapy followed by chemoradiation enables margin-negative resection in 37% of 84 patients with anatomical BRPC (median survival after resection = 40 months), which was diagnosed according to the MD Anderson CC classification (10). In another retrospective study of neoadjuvant GTX followed by SBRT for BRPC (31), an R0 resection rate of 54% (57/106) and median survival time = 16.4 months were achieved with adequate feasibility. Moreover, in a Phase II study of non-metastatic pancreatic cancer, the feasibility and effectiveness of systemic GEM and subsequent full-dose GEM with concurrent radiotherapy was reported for 3/9 R0 resections (32). The treatment regimen was completed in 33 of 39 enrolled patients. Grade 3 to 4 non-hematologic toxicities related to treatment was observed in only 25.6%. The 1-year survival rate was 76% for the nine borderline-resectable patients. Table 2. BRPC clinical trials conducted between 2013 and 2017 Author  Year  Study design  Institution  Radiological central review  Resectability criteria  Stage of object  Number of BRPC points  Neoadjuvant treatment  R0 resection rate of BRPC (including non-resected cases)  MST of BRPC pts (months)  Motoi (66)  2013  PII  Multi  No  Other  R/BR  16  CT (GEM + S-1)  –  –  Kim (33)  2013  PII  Single  –  NCCN  R/BR/URLA  39  CRT (concurrent GEMOX)  –  18.4  Takahashi (34)  2013  PII  Single  –  Other (modified MD Anderson)  R/BR  80  CT (GEM) followed by CRT (concurrent GEM) and subsequent liver perfusion chemotherapy  53%  –  Takeda (36)  2014  PI/II  Multi  No  Other  BR  35  CRT (concurrent GEM)  74%  –  Esnaola (25)  2014  PII  Single  –  Other  BR/UR  13  CT (GEMOX + cetuximab) followed by CRT (concurrent capecitabine)  69%  24.1  Sahora (67)  2014  PII  Single  –  Other  BR/URLA  11  CT (GEM + bevacizumab)  –  –  Jensen (37)  2014  PII  Single  –  Other  BR/URLA  23  CRT (concurrent FP+INFα)  26%  11.5  Holyoake (68)  2016  PI  Multi  No  NCCN  BR  24  Margin intensive SBRT  –  –  Shaib (53)  2016  PI  Single  –  Alliance Trial  BR  13  CT (mFOLFIRINOX) followed by SBRT  62%  11.0  Nywening (69)  2016  PIb  Single  –  AHPBA/SSO/SSAT  BR/URLA  47  CT (FOLFIRINOX + PF-04 136 309)  –  –  Reni (70)  2016  PIb  Single  –  NCCN  BR/URLA  6  CT (GEM + nab-PTX+capecitabine+CDDP)  –  14.5  Katz (51)  2016  PII  Multi  Yes  Alliance Trial  BR  23  CT (mFOLFIRINOX) followed by CRT (concurrent capecitabine)  61%  21.7  Versteijne (27)  2016  ran PII  Multi  No  Other  R/BR  –  CT (GEM) followed by CRT (concurrent GEM) and subsequent CT (GEM) vs. adjuvant CT (GEM)  –  –  Kondo (71)  2017  PI  Multi  No  NCCN  BR/URLA  13  CT (GEM + nab-PTX + S-1)  –  –  Okada (72)  2017  PI  Single  –  NCCN  BR  10  CT (GEM + nab-PTX)  70%  –  Nagakawa (73)  2017  PII  Single  –  Original  BR(Artery)  27  IMRT (concurrent GEM + S-1)  67%  22.4  Okano (38)  2017  PII  Single  –  NCCN  R/BR  24  CRT (concurrent S-1)  –  –  Fiore (28)  2017  PII  Single  –  NCCN  BR/URLA  7  CT (GEMOX) followed by CRT (concurrent GEM)  56%  21.5  Takahashi (39)  2017  PII  Multi  Yes  Other (modified NCCN)  BR  57  CRT (concurrent S-1)  63%  –  Katz (56)  2017  Ran PII  Multi  Yes  Alliance Trial  BR(head)  124  CT (mFOLFIRINOX) with or without SBRT  –  –  Author  Year  Study design  Institution  Radiological central review  Resectability criteria  Stage of object  Number of BRPC points  Neoadjuvant treatment  R0 resection rate of BRPC (including non-resected cases)  MST of BRPC pts (months)  Motoi (66)  2013  PII  Multi  No  Other  R/BR  16  CT (GEM + S-1)  –  –  Kim (33)  2013  PII  Single  –  NCCN  R/BR/URLA  39  CRT (concurrent GEMOX)  –  18.4  Takahashi (34)  2013  PII  Single  –  Other (modified MD Anderson)  R/BR  80  CT (GEM) followed by CRT (concurrent GEM) and subsequent liver perfusion chemotherapy  53%  –  Takeda (36)  2014  PI/II  Multi  No  Other  BR  35  CRT (concurrent GEM)  74%  –  Esnaola (25)  2014  PII  Single  –  Other  BR/UR  13  CT (GEMOX + cetuximab) followed by CRT (concurrent capecitabine)  69%  24.1  Sahora (67)  2014  PII  Single  –  Other  BR/URLA  11  CT (GEM + bevacizumab)  –  –  Jensen (37)  2014  PII  Single  –  Other  BR/URLA  23  CRT (concurrent FP+INFα)  26%  11.5  Holyoake (68)  2016  PI  Multi  No  NCCN  BR  24  Margin intensive SBRT  –  –  Shaib (53)  2016  PI  Single  –  Alliance Trial  BR  13  CT (mFOLFIRINOX) followed by SBRT  62%  11.0  Nywening (69)  2016  PIb  Single  –  AHPBA/SSO/SSAT  BR/URLA  47  CT (FOLFIRINOX + PF-04 136 309)  –  –  Reni (70)  2016  PIb  Single  –  NCCN  BR/URLA  6  CT (GEM + nab-PTX+capecitabine+CDDP)  –  14.5  Katz (51)  2016  PII  Multi  Yes  Alliance Trial  BR  23  CT (mFOLFIRINOX) followed by CRT (concurrent capecitabine)  61%  21.7  Versteijne (27)  2016  ran PII  Multi  No  Other  R/BR  –  CT (GEM) followed by CRT (concurrent GEM) and subsequent CT (GEM) vs. adjuvant CT (GEM)  –  –  Kondo (71)  2017  PI  Multi  No  NCCN  BR/URLA  13  CT (GEM + nab-PTX + S-1)  –  –  Okada (72)  2017  PI  Single  –  NCCN  BR  10  CT (GEM + nab-PTX)  70%  –  Nagakawa (73)  2017  PII  Single  –  Original  BR(Artery)  27  IMRT (concurrent GEM + S-1)  67%  22.4  Okano (38)  2017  PII  Single  –  NCCN  R/BR  24  CRT (concurrent S-1)  –  –  Fiore (28)  2017  PII  Single  –  NCCN  BR/URLA  7  CT (GEMOX) followed by CRT (concurrent GEM)  56%  21.5  Takahashi (39)  2017  PII  Multi  Yes  Other (modified NCCN)  BR  57  CRT (concurrent S-1)  63%  –  Katz (56)  2017  Ran PII  Multi  Yes  Alliance Trial  BR(head)  124  CT (mFOLFIRINOX) with or without SBRT  –  –  BRPC, borderline resectable pancreatic cancer; PI, Phase I; PII, Phase II; ran PII, randomized Phase II; Multi, multicenter; Single, single-center; R, resectable pancreatic cancer; BR, BRPC; URLA, unresectable locally advanced pancreatic cancer; CT, chemotherapy; CRT, chemoradiotherapy; SBRT, stereotactic body radiotherapy; IMRT, Intensity Modulated Radiation Therapy; GEM, gemcitabine; INF, interferon; mFOLFIRINOX, modified FOLFIRINOX; CDDP, cisplatin; nab-PTX, albumin-bound paclitaxel; MST, median survival time. In contrast, neoadjuvant chemoradiation without systemic induction chemotherapy is used to treat BRPC (33–39). Massucco et al. report the outcome of pancreatic resections after GEM with concurrent radiation for locally advanced pancreatic cancer, including BRPC. Gemcitabine of 50 mg/m2 was more feasible than that of 100 mg/m2 being used concurrently with radiation. Of the 18 borderline-resectable patients, a 28% partial response and a 39% R0 resection rate is achieved after neoadjuvant CRT (40). The efficacy and safety of the neoadjuvant capecitabine and concurrent radiation were evaluated in a Phase II study (41). Capecitabine-based chemoradiation is well tolerated and attributed to 12/40 R0 resections, according to the MD Anderson CC classification. Further, the authors report a favorable prognosis of the resected BRPC after CRT, which is comparable with that of resectable pancreatic cancer. Evidence indicates that a combination chemotherapy regimen consisting of oxaliplatin, irinotecan, fluorouracil and leucovorin (FOLFIRINOX) serves as neoadjuvant treatment of BRPC (42), because it exhibits excellent antitumor activity and is now considered standard treatment of patients with metastatic pancreatic cancer (43). In retrospective studies, FOLFIRINOX was evaluated as preoperative therapy for BRPC, anticipating tumor shrinkage and eradication of micrometastasis (44–46). Hosein et al. report the experience of FOLFIRINOX for unresectable or borderline resectable PC. Three (17%) of 18 patients developed febrile neutropenia despite the use of prophylactic filgrastim, however, the regimen’s toxicity was generally manageable. R0 resection was achieved in three (75%) out of four borderline-resectable patients (47). Systemic chemotherapies such as FOLFILINOX or albumin-bound paclitaxel (nab-paclitaxel) plus gemcitabine therapy (GEM + nab-PTX) achieve high-antitumor activity (43,48) and is likely more easily available compared with CRT. The objective response rates of FOLFIRINOX (43) and GEM + nab-PTX (48,49) for metastatic pancreatic cancer were 31.6% and 23–59%, whereas that of gemcitabine which had been the former standard of care was 7–9% (43,48). Systemic chemotherapy alone may provide an alternative for radiotherapy as neoadjuvant treatment of BRPC when the efficacy of treatment, including local effects, is confirmed as not inferior to other radiotherapy treatments. In contrast, more intensive treatment using neoadjuvant-induction chemotherapy using FOIFILINOX or GEM + nab-PTX followed by RT represents another direction for developing treatments for BRPC (50–55). For example, the prospective cohort study conducted by Christians et al. evaluated neoadjuvant FOLFIRINOX and subsequent capecitabine-based chemoradiotherapy for BRPC (50). They concluded that FOLFIRINOX followed by chemoradiation was feasible as neoadjuvant therapy for BRPC and achieved a favorable resection rate = 67% in 18 patients. Grade 3/4 toxicity rate associated with FOLFIRINOX was 75%, and nausea/vomiting was most frequently observed (35.7%). There were no perioperative deaths nor reoperations. The Phase II study conducted by the Alliance for Clinical Trials in Oncology Trial A021101, which is notable for its approach for optimizing study design for BRPC, evaluated the feasibility of preoperatively modified FOLFIRINOX followed by capecitabine-based chemoradiation in patients with BRPC (51). This trial achieved a comparatively high efficacy (R0 resection rate = 64%) in the first intergroup feasibility study of BRPC. The modified FOLFIRINOX protocol, followed by capecitabine-based chemoradiation, was tolerable; however, 64% of the patients experienced ≥Grade-3 adverse events during preoperative treatment. During the preparation of this review, several prospective studies for BRPC were underway (Trial identifires: ClinicalTrials.gov; ISRCTN registry; EORTC clinical trials database.). Most of these studies are Phase I or II. Concurrently, several randomized Phase II or Phase II/III studies comparing different treatments were started to analyze a BRPC cohort. A Phase II study conducted at the University of Pittsburg (NCT02241551) compared mFOLFIRINOX and GEM + nab-PTX as induction chemotherapy before SBRT in the context of developing more intensive treatment using systemic chemotherapy and radiotherapy. In contrast, a few randomized Phase II studies aim to determine the significance of radiotherapy combined with systemic chemotherapy for treating BRPC. Clinical trials in the USA (A021501, NCT02839343) and Europe (PANDAS-PRODIGE44, NCT02676349) are comparing mFOLFIRINOX with or without subsequent radiation as neoadjuvant therapy. The Alliance for Clinical Trials in Oncology uses hypofractioned radiation (56). In contrast, the PANDAS-PRODIGE trial employs capecitabine and concurrent radiation. In comparison, a Phase II/III study (UMIN000026858) compares chemoradiotherapy or chemotherapy alone as neoadjuvant therapy for BRPC. There may be a considerable population not fit for the treatment using both systemic chemotherapy and radiotherapy, considering its intensity. Therefore, the thesis has importance, particularly in an aging population. The results of these studies will set a new direction for the treatment of BRPC in the near future. Phase III study is substantially essential for establishing a standard treatment for BRPC. A randomized Phase III trial comparing a most promising neoadjuvant treatment with upfront surgery seems to be reasonable because a standard treatment using neoadjuvant treatment has not been demonstrate yet. While at the same time, difficult patient-registration is anticipated in Phase III study using upfront surgery as the standard therapy considering recommendation by guidelines of neoadjuvant treatment or physicians’ preference. Then, a Phase III trial using two considered standard treatments may be one of the realistic options in BRPC. In that case, considered treatments must be chosen in view of risk/benefit balances among the most promising neoadjuvant treatments. Either way, feasibility and consensus about the trial concept will be key to successful Phase III trial. Development of a study design for BRPC Delays in standardizing the treatment of BRPC partly result from lack of standardization of clinical trial designs caused by several obstacles. First, BRPC accounts for 5–10% of nonmetastasized PC (8,10). Therefore, the feasibility of conducting a clinical trial requires a global or intergroup study or relaxing the statistical parameters for predicting a sufficient sample size. Second, the definition of BRPC differs among guidelines. In particular, the definition of tumor–portal vein contact differs so much that it could bias the results of the trial. If the definitions of BRPC are not standardized, this should be clearly stated in the protocol to ensure that the results of trials can be compared. Further, the interpretation of multidetector CT (MDCT) findings varies among institutions. Accordingly, all MDCTs used for registration should ideally be diagnosed through central diagnosis. Third, the indications for surgical resection after neoadjuvant treatment are not standardized. The tumor–vessel interactions of BRPC rarely improves to those of resectable PC after several months of preoperative treatment (12,46). Most BRPC remains borderline resectable. Moreover, some cases of BRPC appear to be unresectable PC after neoadjuvant therapy, and radiological resectability status does not necessarily correspond with the possibility of R0 resection after neoadjuvant treatment. Therefore, indications for surgical resection after neoadjuvant treatment should be stated in a protocol. However, the details of surgical indications are rarely stated in the studies analyzed here. The heterogeneity of clinical trial designs for BRPC is reported by Katz et al. Katz et al. reviewed 23 studies published from 2001 to 2012, which include 35% prospective studies (11). For example, unambiguous inconsistency was observed in the stages studied, staging classifications, indications for surgery, and the endpoint defined to evaluate treatment. They advocated the necessity of standardizing clinical trial design in all future studies of BRPC. Our present study found that 54% of the trials are prospective, indicating an encouraging trend that promises to achieve a standardized design of BRPC clinical trials. In this review, 37 studies for pancreatic cancer, including BRPC, were analyzed. Of the 37 studies, 20 prospective studies are listed in Table 2. The number of patients with BRPC was <30 in 13 (65%) of the 20 trials, and >50 in three studies (Fig. 1). These numbers likely attest to the infrequent occurrence of BRPC and to the inability to identify a Phase III study (Fig. 2). Figure 1. View largeDownload slide Sample sizes of the 20 clinical trials for BRPC reported between 2013 and 2017. The sample sizes of 13 (65%) of the 20 trials were <30 and >50 in three. Figure 1. View largeDownload slide Sample sizes of the 20 clinical trials for BRPC reported between 2013 and 2017. The sample sizes of 13 (65%) of the 20 trials were <30 and >50 in three. Figure 2. View largeDownload slide Study phases of the 20 clinical trials for BRPC reported between 2013 and 2017. Approximately 50% of the 20 trials were Phase II, followed by Phase I. There were two randomized Phase II studies, and a Phase III study was not identified by our strategic literature search. PI, Phase I; PII, Phase II, random PII, randomized Phase II; PIII, Phase III. Figure 2. View largeDownload slide Study phases of the 20 clinical trials for BRPC reported between 2013 and 2017. Approximately 50% of the 20 trials were Phase II, followed by Phase I. There were two randomized Phase II studies, and a Phase III study was not identified by our strategic literature search. PI, Phase I; PII, Phase II, random PII, randomized Phase II; PIII, Phase III. Trials targeting BRPC alone are increasing, but the number remains small, partly because of its rarity. Many studies (60%) target BRPC as well as resectable or unresectable localized pancreatic cancer. The populations are as follows: patients with resectable or borderline resectable PC, patients with borderline resectable or unresectable locally advanced PC, and patients with localized PC independent of resectability (Fig. 3). The target of the study could be changed by treatment strategy; however, clinical trials of only BRPC are urgently required to establish a standard treatment. Figure 3. View largeDownload slide Resectability stage object of the 20 clinical trials for BRPC reported between 2013 and 2017. Many studies (60%) targeted BRPC as well as resectable or unresectable localized pancreatic cancer. Figure 3. View largeDownload slide Resectability stage object of the 20 clinical trials for BRPC reported between 2013 and 2017. Many studies (60%) targeted BRPC as well as resectable or unresectable localized pancreatic cancer. When the resectability criteria used in all 37 studies were examined, the NCCN classification was used most frequently, followed by the AHPBA/SSO/SSAT classification (Fig. 4a). In 20 prospective clinical trials, the Alliance Trial classification was the second most frequent criteria, while the Alliance Trial criteria were formulated to promote global standardization of the resectability classifications (Fig. 4b). In contrast, seven of the clinical trials for BRPC applied the original classifications for diagnosing surgical resectability. Standardization of resectability criteria is a pressing issue for managing BRPC. Figure 4. View largeDownload slide (a) Resectability criteria used in 37 studies that examined neoadjuvant treatment of BRPC. The NCCN classification criteria were used most frequently, followed by the AHPBA/SSO/SSAT classification. (b) Resectability criteria used in 20 prospective trials of BRPC. The NCCN classification was used most frequently. In contrast to the results of the 37 studies, the Alliance Trial classification criteria were the second most frequently used in the prospective clinical trials. NCCN, National Comprehensive Cancer Network; AHPBA, American Hepato-Pancreato-Biliary Association; SS0, Society of Surgical Oncology; SSAT; Society for Surgery of the Alimentary Tract. Figure 4. View largeDownload slide (a) Resectability criteria used in 37 studies that examined neoadjuvant treatment of BRPC. The NCCN classification criteria were used most frequently, followed by the AHPBA/SSO/SSAT classification. (b) Resectability criteria used in 20 prospective trials of BRPC. The NCCN classification was used most frequently. In contrast to the results of the 37 studies, the Alliance Trial classification criteria were the second most frequently used in the prospective clinical trials. NCCN, National Comprehensive Cancer Network; AHPBA, American Hepato-Pancreato-Biliary Association; SS0, Society of Surgical Oncology; SSAT; Society for Surgery of the Alimentary Tract. Neoadjuvant CT followed by RT or CRT was most frequently administered to patients with BRPC (Fig. 5). Radiation was used in 70% of the 37 studies, which indicates that radiotherapy is considered to contribute to the treatment for BRPC subject to local failure. Figure 5. View largeDownload slide Neoadjuvant treatment used in 37 studies, which examined neoadjuvant treatment of BRPC. Neoadjuvant CT followed by RT or CRT was most frequently applied to treat BRPC. Radiation was used in 70% of the 37 studies. CT, chemotherapy; RT, radiotherapy; CRT, chemoradiotherapy. Figure 5. View largeDownload slide Neoadjuvant treatment used in 37 studies, which examined neoadjuvant treatment of BRPC. Neoadjuvant CT followed by RT or CRT was most frequently applied to treat BRPC. Radiation was used in 70% of the 37 studies. CT, chemotherapy; RT, radiotherapy; CRT, chemoradiotherapy. A review of 37 studies published from 2013 to 2017 reveals that multi-institutional studies increased. Conducting multi-institutional study is essential for Phase III studies of such a rare disease. Moreover, multi-institutional studies for BRPC require additional infrastructure such as centralized radiological and pathological reviews. However, few multi-institutional studies implemented a centralized radiological review. In summary, the number of clinical trials for BRPC has increased from 23 in the former 12 years to 37 in the recent 5 years, but few are randomized trials. However, a few clinical trials were conducted that were optimized for BRPC. Standardization of classifications and improvement of infrastructure are required for further promotion of clinical trials for BRPC, which will accelerate the development of a standardized treatment for BRPC. Surgical resection to treat BRPC Surgery for BRPC can be performed with techniques developed over the years; however, special care is required for surgical indications such as the approach to the corresponding artery and concomitant vessel resection. After neoadjuvant therapy, radiological tumor morphology does not reflect antitumor effects. The RECIST tumor response does not match the pathological response after neoadjuvant treatment (12,46), partly because radiological morphology can be affected by treatment effects such as edema or inflammation. Morphological changes usually follow soon after treatment, particularly after radiotherapy. Further, resectability status according to the classification after neoadjuvant treatment does not represent actual resectability (46). Even when the tumor does not seem to respond to the preceding treatment, or is not down-staged after treatment, R0 resection may be achieved. Therefore, unless progressive disease, defined according to the RECIST rules, is observed, it is preferable to perform laparotomy. The trend of the serum CA19-9 value after neoadjuvant treatment may help patients to decide to undergo laparotomy, particularly those with BRPC that does not respond to radiotherapy (4,57,58). The surgeon must first determine whether the tumor is resectable, because the tumor contacts the surrounding major artery or vein. Resectability should be judged before the procedure passes the point of no return. In particular, the retroperitoneal SMA margin likely results in a higher rate of microscopic positive surgical margins because of its close proximity to the head of the pancreas, while a positive SMA margin frequently causes local failure. Therefore, an artery-first approach for SMA is now frequently used to instantaneously determine resectability and to acquire a higher R0-resection rate for pancreaticoduodenectomy (59,60). Moreover, several clinical studies validate the effect of the ‘artery-first approach’ in pancreaticoduodenectomy for pancreatic cancer (NCT03224832, NCT02803814, NCT01332773). In BRPC, resection of the PV/SMV is often required and is expected when required for R0 resection. Venous criteria of resectability guidelines presuppose the feasibility of safe and complete resection and reconstruction (61). A large meta-analysis shows that addition of venous resection does not increase morbidity, mortality or decrease 5-year overall survival comparing pancreatectomy without venous resection (15,62). In contrast, increased morbidity and mortality occur in concomitant arterial resection with pancreatectomy, although the prognosis of patients after the combined arterial and pancreatic resections is superior compared with those who did not undergo pancreatic resection (63,64). Therefore, concomitant arterial resection should be limited to highly selected patients and performed in specialized centers. BRPC located in the pancreas body often contacts the celiac axis or common hepatic artery. Distal pancreatectomy with celiac axis resection (DP-CAR) or a modified Appleby resection can remove the tumor, the corresponding celiac axis, and the common hepatic artery as en block without reconstruction using the collateral artery of the pancreatic arcade (18,65). The surgeries are uncommon but sometimes performed in specialized centers for treating pancreatic cancer. The modified Appleby procedures or DP-CAR may lead to improved safety after en block tumor and artery resections and facilitate resections of BRPC or unresectable PC. Therefore, the feasibility and effects of the aforementioned surgeries should be evaluated in clinical studies of BRPC. Conclusions BRPC is one of the targets of multidisciplinary approaches using neoadjuvant treatment of pancreatic cancer, because it is frequently associated with locoregional or systemic failure, even if the tumor is resected. Therefore, a multidisciplinary team including a surgeon, oncologist, radiation oncologist and radiologist is critically important for the optimum treatment for BRPC. Presently, neoadjuvant chemotherapy followed by chemoradiation is the major treatment strategy. Moreover, a number of clinical trials of BRPC are in progress. Although standardization of classifications and improvement of infrastructure are required, efficient treatment of BRPC likely will be developed in the near future and will help increase the cure rate of this deadly disease. Funding This work is supported by the Practical Research for Innovative Cancer Control from Japan Agency for Medical Research and Development, AMED (15Ack0106154h0001). Conflict of interest statement None declared. 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