Clinical significance of defining borderline resectable pancreatic cancer

Since the introduction of the concept of borderline resectable pancreatic cancer (BRPC), various definitions of this disease entity have been suggested. However, there are several obstacles in defining this disease category. The current diagnostic criteria of BRPC mainly focuses on its expanded ‘technical resectability’; however, they are difficult to interpret because of their ambiguity using potential subjective or arbitrary terminology, In addition, limitations in current imaging technology and a lack of evidence in radiological-pathological-clinical correlation make it difficult to refine the criteria. On the other hand, neoadjuvant treatment is usually applied to increase the R0 resection rate of BRPC focusing on the ‘oncological curability’. However, evidence is needed concerning the effect of neoadjuvant treatment by quality-controlled prospective randomized clinical trials based on a standardized radiologic and pathologic reporting system. In conclusion, there are two aspects in the current concept of BRPC, which are technical resectability and oncological curability. Although the recent evolution of surgical techniques is expanding the scope of technical resectability, it should not be overlooked that the disease entity must be defined based on the evidence of oncological curability.     

Gemcitabine based neoadjuvant chemoradiotherapy therapy in patients with borderline resectable pancreatic cancer

BackgroundSurgical resection is the only curative treatment for pancreatic cancer, but surgical outcomes for borderline resectable pancreatic cancer (BRPC) are generally poor because of the complexity of the surgery and the advanced nature of the tumor. The aim of this study was to evaluate whether neoadjuvant concurrent chemoradiation therapy (CCRT) in BRPC patients could improve surgical outcome.MethodsBaseline characteristics and treatment outcomes for patients who underwent surgery for BRPC with (CCRT (+) group) and without neoadjuvant treatment (CCRT (?) group) were retrospectively compared. Treatment outcomes measured included overall survival, recurrence-free survival, and perioperative complications.ResultsA total of 30 patients were included in the CCRT (+) group and 21 patients in the CCRT (?) group. Baseline characteristics were not different before CCRT, but pathological examination after resection revealed reduced tumor size and a lower neurovascular invasion rate in the CCRT (+) group. Overall median survival time was 45.0 months in the CCRT (+) group and 23.5 months in the CCRT (?) group (p = 0.045). The CCRT (+) group had a lower recurrence rate (50.0% vs. 81.0%; p = 0.024) and a longer median disease-free survival period (21.0 months vs. 10.6 months; p = 0.004) than the CCRT (?) group. Perioperative complication rates were not different between the two groups.ConclusionsNeoadjuvant chemoradiation therapy combined with surgical resection yielded better treatment outcomes in patients with BRPC compared with surgery alone. Further larger prospective clinical trials with well defined enrollment criteria and treatment plan are needed.     

Clinical implications of the serum CA19-9 level in “biological borderline resectability” and “biological downstaging” in the setting of preoperative chemoradiation therapy for pancreatic cancer

BackgroundBiological factors are emphasized in borderline resectable pancreatic cancer (BRPC), and CA19-9 is an important factor for biological borderline resectability (b-BR). The aim of this study was to investigate the cut-off value of CA19-9 for biological borderline resectability and “biological downstaging” in chemoradiation therapy (CRT) for pancreatic cancer (PC).MethodsA total of 407 patients with anatomically resectable PC (a-R) and BRPC (a-BR) received preoperative gemcitabine-based CRT. The b-BR was determined, according to the CA19-9 value prior to preoperative CRT (pre-CA19-9), as the subgroup of a-R cases in which the survival was comparable with that in a-BR cases. “Biological downstaging” was determined based on prognostic analyses regarding the CA19-9 value after preoperative CRT (post-CA19-9) in association with the survival of R cases (a-R cases without the b-BR factor).ResultsThe 5-year survival of a-R patients with pre-CA19-9 > 120 U/mL was comparable with that of a-BR patients (44% vs 34%, p = 0.082). The survival of b-BR patients with post-CRT CA19-9 ≤ 37 U/mL (normalized) was comparably favorable with that of R patients (56% vs 65%, p = 0.369). The incidence of distant recurrence was higher in b-BR patients without post-CA19-9 normalization than in those with post-CA19-9 normalization (70% vs 50%, p = 0.003), while the incidence of local recurrence was comparable between these two groups (12% vs 13%, p = 0.986).ConclusionsBiological BRPC was determined to be an anatomically resectable disease with pre-CA19-9 > 120 U/mL, and post-CA19-9 normalization indicated “biological downstaging” in b-BR in the preoperative CRT strategy.     

“可能切除的”胰腺癌的外科治疗策略

“可能切除的”胰腺癌介于“可切除”与“不可切除”之间,其定义的主要内涵是肠系膜上静脉、门静脉、肠系膜上动脉或肝总动脉是否为肿瘤侵犯及是否可切除重建,是目前的热点课题。“可能切除的”胰腺癌所涉及的外科相关问题包括：联合血管切除的安全性、有效性;淋巴清扫范围;标本切缘检测的标准化等。治疗方面建议对此类患者行新辅助放化疗,以增加R0切除的几率及可能性,但具体方案尚不统一,亦无RCT研究佐证。在目前多学科治疗模式及理念下,R1切除的价值及意义值得重新审视。     

Selection criteria in resectable pancreatic cancer: A biological and morphological approach

Pancreatic ductal adenocarcinoma (PDA) remains one of the most aggressive tumors with a low rate of survival. Surgery is the only curative treatment for PDA, although only 20% of patients are resectable at diagnosis. During the last decade there was an improvement in survival in patients affected by PDA, possibly explained by the advances in cancer therapy and by improve patient selection by pancreatic surgeons. It is necessary to select patients not only on the basis of surgical resectability, but also on the basis of the biological nature of the tumor. Specific preoperative criteria can be identified in order to select patients who will benefit from surgical resection. Duration of symptoms and level of carbohydrate antigen 19.9 in resectable disease should be considered to avoid R1 resection and early relapse. Radiological assessment can help surgeons to distinguish resectable disease from borderline resectable disease and locally advanced pancreatic cancer. Better patient selection can increase survival rate and neoadjuvant treatment can help surgeons select patients who will benefit from surgery.     

Validation of Group B Borderline Resectable Pancreatic Cancer: Retrospective Analysis

Background/Aims

Among borderline resectable pancreatic cancer (BRPC), group B BRPC patients have findings that are suggestive but not diagnostic of metastasis. In this study, we attempted to validate whether group B could truly be categorized as a borderline resectable group.

Methods

We placed the BRPC patients into group A or group B. The survival outcomes were compared between the groups.

Results

A total of 53 patients with pancreatic adenocarcinoma was classified as either group A or B borderline resectable. In group A, 23 (60.5%) of 38 patients underwent pancreatectomy after concurrent chemoradiotherapy or chemotherapy, but in group B, only five (33.3%) of 15 patients underwent pancreatectomy, mainly because of the progression of suspected distant metastasis. There was a significant difference in overall survival (OS) between group A and B patients (median OS, 21.2 months vs 10.2 months, respectively; p=0.007). Of the patients who underwent pancreatectomy, group B had a higher recurrence rate compared to group A (recurrence rate: 11 of 23 patients [47.8%] vs five of five patients [100%], respectively; p=0.033).

Conclusions

This report is the first to validate the definition of BPRC. Group B had much worse outcomes, and whether group B BRPC can be categorized as BRPC together with group A is questionable.     

Borderline resectable pancreatic cancer: rationale for multidisciplinary treatment

Background

Borderline resectable pancreatic cancer (BRPC) appears to be most frequently related to a positive surgical margin and has a poor prognosis after resection. However, few reports are available on differences in tumor characteristics and prognoses among resectable pancreatic cancer (PC), BRPC, and unresectable PC.

Methods

Records of 133 patients resected for pancreatic ductal adenocarcinoma and 185 patients treated as locally advanced PC (LAPC) were reviewed.

Results

Twenty-four patients who initially underwent resection (BRPC-s) and 10 patients who were initially treated as LAPC (BRPC-n) met the criteria for BRPC. Prognosis of BRPC was significantly better than that of unresectable PC, but was significantly worse than that of resectable PC. BRPC-s showed more frequent nerve plexus invasion (P < 0.01), portal vein invasion (P < 0.01), and loco-regional recurrence (P = 0.03) than resectable PC. The positive surgical margin rate was not significantly higher in BRPC-s (29%) than in resectable PC (19%) (P = 0.41).

Conclusions

BRPC had a poorer prognosis with more local failure than resectable PC although prognosis of BRPC was significantly better than that of unresectable PC. Considering the tumor and treatment characteristics, multidisciplinary treatment including resection is required for BRPC.     

Neoadjuvant strategies for pancreatic cancer

Pancreatic cancer (PC) is the fourth cause of cancer death in Western countries, the only chance for long term survival is an R0 surgical resection that is feasible in about 10%-20% of all cases. Five years cumulative survival is less than 5% and rises to 25% for radically resected patients. About 40% has locally advanced in PC either borderline resectable (BRPC) or unresectable locally advanced (LAPC). Since LAPC and BRPC have been recognized as a particular form of PC neoadjuvant therapy (NT) has increasingly became a valid treatment option. The aim of NT is to reach local control of disease but, also, it is recognized to convert about 40% of LAPC patients to R0 resectability, thus providing a significant improvement of prognosis for responding patients. Once R0 resection is achieved, survival is comparable to that of early stage PCs treated by upfront surgery. Thus it is crucial to look for a proper patient selection. Neoadjuvant strategies are multiples and include neoadjuvant chemotherapy (nCT), and the association of nCT with radiotherapy (nCRT) given as either a combination of a radio sensitizing drug as gemcitabine or capecitabine or and concomitant irradiation or as upfront nCT followed by nRT associated to a radio sensitizing drug. This latter seem to be most promising as it may select patients who do not go on disease progression during initial treatment and seem to have a better prognosis. The clinical relevance of nCRT may be enhanced by the application of higher active protocols as FOLFIRINOX.     

Borderline resectable pancreatic cancer

Opinion statement Rigorous criteria to define "borderline resectable" pancreatic cancer are required for appropriate patient accrual into clinical trials that examine the utility of chemotherapy and/or chemoradiation that will be delivered prior to pancreatic resection for exocrine cancer. At our institution, tumor abutment of less than or equal to 180 degrees (≤ 50% of the vessel circumference) of the superior mesenteric artery, short segment abutment or encasement (≥50% of the vessel circumference) of the common hepatic artery (typically at the gastroduodenal artery origin), or segmental venous occlusion are used to categorize a pancreatic tumor as borderline resectable. These patients are at a high risk for margin positive resection with initial surgery; therefore, we favor a treatment schema that incorporates preoperative (neoadjuvant) therapy with systemic chemotherapy and chemoradiation. Patients whose tumors show radiographic stability or regression that are often accompanied by an improvement in serum tumor markers are candidates for pancreaticoduodenectomy. A prospective multicenter clinical trial with well-defined eligibility criteria may help decide the best overall treatment strategy for these patients. Vascular resection and reconstruction may be required in patients with borderline resectable tumors, and surgery should be performed at centers with expertise in such complex pancreatic resections.     

Novel directions in neoadjuvant therapy for pancreas adenocarcinoma

Surgical resection of pancreatic carcinoma has long represented the only viable option for a potential cure of pancreas cancer. The use of adjuvant chemotherapy post-resection has been established in treating micro metastases and prolonging disease-free survival. However, studies of neoadjuvant therapy have not come to any definitive conclusion regarding the overall efficacy of such treatment, despite the theoretical benefits. In this review, we examine the historical precedent as well as the current state of affairs regarding neoadjuvant therapy in resectable and borderline resectable pancreatic adenocarcinoma. In addition, we review the definitions for resectable and borderline resectable disease and highlight key areas of clinical investigation in the field and summarize the major ongoing neoadjuvant studies focused on resectable pancreatic adenocarcinoma.     

Korean clinical practice guideline for pancreatic cancer 2021: A summary of evidence-based,multi-disciplinary diagnostic and therapeutic approaches

Pancreatic cancer is the eighth most common cancer and the fifth most common cause of cancer-related death in Korea. To enable standardization of management and facilitate improvements in outcome, a total of 53 multi-disciplinary experts in gastroenterology, surgery, medical oncology, radiation oncology, radiology, nuclear medicine, and pathology in Korea developed new recommendations that integrate the most up-to-date, evidence-based research findings and expert opinions. Recommendations were made on imaging diagnosis, endoscopic management, surgery, radiotherapy, palliative chemotherapy, and specific management procedures, including neoadjuvant treatment or adjuvant treatment for patients with resectable, borderline resectable, and locally advanced unresectable pancreatic cancer.This is the English version of the Korean clinical practice guideline for pancreatic cancer 2021. This guideline includes 20 clinical questions and 32 statements. This guideline represents the most standard guideline for the diagnosis and treatment of patients with pancreatic ductal adenocarcinoma in adults at this time in Korea. The authors believe that this guideline will provide useful and informative advice.     

Clinical features and treatment outcome of borderline resectable pancreatic head/body cancer: a multi-institutional survey by the Japanese Society of Pancreatic Surgery

Background

Optimal treatment types and prognosis for patients with borderline resectable pancreatic cancer (BRPC) remain unclear because of the lack of studies involving large series of patients.

Methods

We retrospectively analyzed various prognostic factors for 624 BRPC (pancreatic head/body) patients treated from June 2002 to May 2007, by distributing questionnaires to member institutions of the Japanese Society of Pancreatic Surgery in 2010. BRPC was defined according to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines (2009).

Results

Among 624 patients, 539 (86.4 %) underwent curative-intent resection, showing an R0 resection rate of 65.9 %. The 3- and 5-year survival rates were 16.1 and 9.9 % in all patients, 22.8 and 12.5 % in the resected patients, and 4.4 and 0 % (P < 0.0001) in the unresected patients, respectively. The following factors influencing survival in all patients were selected as independent prognostic factors using multivariate analysis: major arterial involvement on imaging study; preoperative treatment; surgical resection; and postoperative chemotherapy. Among the resected cases, multivariate analysis revealed that major arterial involvement and remnant tumor status were independent prognostic factors.

Conclusion

BRPC included two distinct categories of tumors influencing survival: those with portal vein/superior mesenteric vein invasion alone and those with major arterial invasion, which was the most exacerbating factor in the analysis.     

Combined Multichannel Intraluminal Impedance-pH (MII-pH): Multicenter Report of Normal Values from 117 Children

Pancreatic cancer is the fourth leading cause of cancer deaths in the USA. Although some patients will present with premalignant pancreatic lesions (i.e., intraductal papillary mucinous neoplasms) or localized tumors amenable to curative resection, the majority of patients will unfortunately present with technically unresectable or metastatic disease. This review of the recent medical literature will discuss the optimal work-up and management of premalignant pancreatic lesions and the surgical management of localized, borderline resectable, and locally advanced (i.e., unresectable) pancreatic tumors. It will focus on new criteria used to define surgical “resectability,” the significance and clinical impact of surgical margins, the role of multimodality therapy in the management of patients with borderline resectable or locally advanced tumors, the role of surgery for local or distant recurrence, and minimally invasive surgical approaches.     

Development of chemotherapy and significance of conversion surgery after chemotherapy in unresectable pancreatic cancer

While surgery currently remains the only potentially curative treatment available for pancreatic cancer, only 20% to 30% of patients have resectable disease at diagnosis. Recently, with the introduction of intensive chemotherapy regimens such as oxaliplatin, irinotecan, fluorouracil plus leucovorin (FOLFIRINOX) and gemcitabine plus nab‐paclitaxel, for the treatment of unresectable pancreatic cancer, the antitumor activity and overall survival in patients with pancreatic cancer have dramatically improved. These advances in intensive chemotherapy have led to the possibility of conversion of unresectable disease to resectable disease, and it has been reported that more than 20% of pancreatic cancer patients with unresectable locally advanced disease at diagnosis undergo successful conversion surgery after FOLFIRINOX therapy. In metastatic pancreatic cancer, resection for the primary lesion of pancreatic cancer may show some benefits for some patients with complete resolution of metastases by chemotherapy. Furthermore, surgical resection in some patients with only a few metastases, so‐called oligometastases, have also been reported. Conversion surgery is becoming increasingly possible with the introduction of intensive chemotherapies, however, the actual clinical benefits of resection in such cases has not yet been sufficiently investigated. The long‐term safety, feasibility and outcomes still need to be investigated in well‐designed, multi‐institutional studies on a large number of patients.     

Neoadjuvant chemoradiotherapy for locally advanced pancreas cancer rarely leads to radiological evidence of tumour regression

Background: Neo-adjuvant chemo-radiotherapy has been proposed to improve resectability of locally-advanced pancreatic cancer (LAPC). However, the ability of neo-adjuvant therapy to induce radiological tumour regression has not been reported.Methods: Pre-and post-treatment computed tomography (CT) scans of patients undergoing neo-adjuvant chemo-radiotherapy for LAPC were reviewed. LAPC was sub-classified into borderline resectable disease [≤180° involvement of the superior mesenteric artery (SMA); short-segment encasement/abutment of the common hepatic artery; or tumour-associated deformity, abutment or short-segment occlusion of the superior mesenteric vein (SMV)/ portal vein (PV) that was amenable to vascular resection and reconstruction] and locally advanced un-resectable pancreatic cancer (vascular involvement more than that described for borderline resectable pancreatic cancer). The radiological response and surgical resection rates were assessed.Results: Sixteen patients received neo-adjuvant therapy for LAPC during 2005–2008. Regression of major vascular involvement, i.e. un-encasement or regression of abutment of any involved vessels was not observed in any patient. Pre-and post-treatment tumour densities were not statistically different. Fifty per cent of patients with borderline resectable disease and none of the patients with locally advanced un-resectable pancreatic cancer eventually underwent surgical resection.Conclusion: Neo-adjuvant treatment does not induce radiological tumour regression of LAPC with major vascular involvement. Patient selection for neo-adjuvant trial enrolment should remain focused on borderline disease which may have a potential for surgical resection.     

Borderline resectable pancreatic cancer: Definitions and management

Pancreatic cancer is the fourth leading cause of cancer death in the United States. While surgical resection remains the only curative option, more than 80% of patients present with unresectable disease. Unfortunately, even among those who undergo resection, the reported median survival is 15-23 mo, with a 5-year survival of approximately 20%. Disappointingly, over the past several decades, despite improvements in diagnostic imaging, surgical technique and chemotherapeutic options, only modest improvements in survival have been realized. Nevertheless, it remains clear that surgical resection is a prerequisite for achieving long-term survival and cure. There is now emerging consensus that a subgroup of patients, previously considered poor candidates for resection because of the relationship of their primary tumor to surrounding vasculature, may benefit from resection, particularly when preceded by neoadjuvant therapy. This stage of disease, termed borderline resectable pancreatic cancer, has become of increasing interest and is now the focus of a multi-institutional clinical trial. Here we outline the history, progress, current treatment recommendations, and future directions for research in borderline resectable pancreatic cancer.     

Management of borderline resectable pancreatic adenocarcinoma

Pancreatic adenocarcinoma is the fourth most common cause of cancer-related death among U.S. men and women. Despite much effort in translational research, pancreatic adenocarcinoma remains a challenging disease with an overall 5-year survival rate less than 5%. To date, the only potentially curative treatment for managing pancreatic adenocarcinoma is surgical resection. However, more than 80% of patients are deemed either unresectable or metastatic upon diagnosis. For borderline resectable disease, although there is no high-level evidence supporting its use, an initial approach involving neoadjuvant therapy is preferred, as opposed to immediate surgery. In this year's ASCO Gastrointestinal Cancers Symposium, several studies were presented with approaches towards treating borderline resectable pancreatic adenocarcinoma. Retrospective studies (Abstract #280, #304, #327) were presented and showed that neoadjuvant chemoradiation were associated with higher rates of negative margin resection and better survival. The tolerability of accelerated fraction radiotherapy with concomitant capecitabine was demonstrated in a phase I study (Abstract #329). More effective therapeutic approaches and prospective studies are needed for this devastating illness. This highlight article will focus on the management of borderline resectable pancreatic adenocarcinoma.     

Pathologic tumor response to neoadjuvant therapy in borderline resectable pancreatic cancer

BackgroundPrevious studies have demonstrated the prognostic significance of pathologic tumor response in pancreatic adenocarcinoma following neoadjuvant therapy (NAT). The aim of this study was to determine the incidence of significant pathologic response to NAT in borderline resectable pancreatic cancer (BRPC), and association of NAT regimen and other clinico-pathologic characteristics with pathologic response.MethodsPatients with BRPC who underwent NAT and pancreatic resection between January 2012 and June 2017 were included. Pathologic response was assessed on a qualitative scale based on the College of American Pathologists grading system. Demographics and baseline characteristics, oncologic treatment, pathology, and survival outcomes were compared.ResultsSeventy-one patients were included for analysis. Four patients had complete pathologic responses (tumor regression score 0), 12 patients had marked responses (score 1), 42 had moderate responses (score 2), and 13 had minimal responses (score 3). Patients with complete or marked responses were more likely to have received neoadjuvant gemcitabine chemoradiation (62.5%, 38.1%, and 23.1% of the complete/marked, moderate, and minimal response groups, respectively; P = 0.04). Of the complete/marked, moderate, and minimal response groups, margins were negative in 75.0%, 78.6%, and 46.2% (P = 0.16); node negative disease was observed in 87.5%, 54.8%, and 15.4% (P < 0.01); and median overall survival was 50.0 months, 31.7 months, and 23.2 months (P = 0.563). Of the four patients with pathologic complete responses, three were disease-free at 66.1, 41.7 and 31.4 months, and one was deceased with metastatic liver disease at 16.9 months.ConclusionsA more pronounced pathologic tumor response to NAT in BRPC is correlated with node negative disease, but was not associated with a statistically significant survival benefit in this study.     

International consensus on definition and criteria of borderline resectable pancreatic ductal adenocarcinoma 2017

This statement was developed to promote international consensus on the definition of borderline resectable pancreatic ductal adenocarcinoma (BR-PDAC) which was adopted by the National Comprehensive Cancer Network (NCCN) in 2006, but which has changed yearly and become more complicated. Based on a symposium held during the 20th meeting of the International Association of Pancreatology (IAP) in Sendai, Japan, in 2016, the presenters sought consensus on issues related to BR-PDAC. We defined patients with BR-PDAC according to the three distinct dimensions: anatomical (A), biological (B), and conditional (C). Anatomic factors include tumor contact with the superior mesenteric artery and/or celiac artery of less than 180° without showing stenosis or deformity, tumor contact with the common hepatic artery without showing tumor contact with the proper hepatic artery and/or celiac artery, and tumor contact with the superior mesenteric vein and/or portal vein including bilateral narrowing or occlusion without extending beyond the inferior border of the duodenum. Biological factors include potentially resectable disease based on anatomic criteria but with clinical findings suspicious for (but unproven) distant metastases or regional lymph nodes metastases diagnosed by biopsy or positron emission tomography-computed tomography. This also includes a serum carbohydrate antigen (CA) 19–9 level more than 500 units/ml. Conditional factors include the patients with potentially resectable disease based on anatomic and biologic criteria and with Eastern Cooperative Oncology Group (ECOG) performance status of 2 or more. The definition of BR-PDAC requires one or more positive dimensions (e.g. A, B, C, AB, AC, BC or ABC). The present definition acknowledges that resectability is not just about the anatomic relationship between the tumor and vessels, but that biological and conditional dimensions are also important. The aim in presenting this consensus definition is also to highlight issues which remain controversial and require further research.     

New challenges in perioperative management of pancreatic cancer

Pancreatic ductal adenocarcinoma(PDAC)is the fourth leading cause of cancer-related death in the industrialized world.Despite progress in the understanding of the molecular and genetic basis of this disease,the5-year survival rate has remained low and usually does not exceed 5%.Only 20%-25%of patients present with potentially resectable disease and surgery represents the only chance for a cure.After decades of gemcitabine hegemony and limited therapeutic options,more active chemotherapies are emerging in advanced PDAC,like 5-Fluorouracil,folinic acid,irinotecan and oxaliplatin and nab-paclitaxel plus gemcitabine,that have profoundly impacted therapeutic possibilities.PDAC is considered a systemic disease because of the high rate of relapse after curative surgery in patients with resectable disease at diagnosis.Neoadjuvant strategies in resectable,borderline resectable,or locally advanced pancreatic cancer may improve outcomes.Incorporation of tissue biomarker testing and imaging techniques into preoperative strategies should allow clinicians to identify patients who may ultimately achieve curative benefit from surgery.This review summarizes current knowledge of adjuvant and neoadjuvant treatment for PDAC and discusses the rationale for moving from adjuvant to preoperative and perioperative therapeutic strategies in the current era of more active chemotherapies and personalized medicine.We also discuss the integration of good specimen collection,tissue biomarkers,and imaging tools into newly designed preoperative and perioperative strategies.