Comprehensive multimodal management of borderline resectable pancreatic cancer:Current status and progress

Borderline resectable pancreatic cancer(BRPC)is a complex clinical entity with specific biological features.Criteria for resectability need to be assessed in combination with tumor anatomy and oncology.Neoadjuvant therapy(NAT)for BRPC patients is associated with additional survival benefits.Research is currently focused on exploring the optimal NAT regimen and more reliable ways of assessing response to NAT.More attention to management standards during NAT,including biliary drainage and nutritional support,is needed.Surgery remains the cornerstone of BRPC treatment and multidisciplinary teams can help to evaluate whether patients are suitable for surgery and provide individualized management during the perioperative period,including NAT responsiveness and the selection of surgical timing.

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 longterm 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 multiinstitutional clinical trial. Here we outline the history, progress, current treatment recommendations, and future directions for research in borderline resectable pancreatic cancer.

Pancreaticoduodenectomy for borderline resectable pancreatic head cancer with a modified artery-first approach technique

BACKGROUND： The treatment of borderline resectable pancreatic head cancer（BRPHC） is still controversial and challenging. The artery-first approaches are described to be the important options for the early determination. Whether these approaches can achieve an increase R0 rate, better bleeding control and increasing long-term survival for BRPHC are still controversial. We compared a previously reported technique, a modified artery-first approach（MAFA）, with conventional techniques for the surgical treatment of BRPHC.METHODS： A total of 117 patients with BRPHC undergone pancreaticoduodenectomy（PD） from January 2013 to June 2015 were included. They were divided into an MAFA group（n=78） and a conventional-technique group（n=39）. Background characteristics, operative data and complications were compared between the two groups.RESULTS： Mean operation time was significantly shorter in the MAFA group than that in the conventional-technique group（313 vs 384 min; P=0.014）; mean volume of intraoperative blood loss was significantly lower in the MAFA group than that in the conventional-technique group（534 vs 756 m L; P=0.043）; and mean rate of venous resection was significantly higher in the conventional-technique group than that in the MAFA group（61.5% vs 35.9%; P=0.014）. Pathologic data, early mortality and morbidity were not different significantly between the two groups.CONCLUSIONS： MAFA is safe, simple, less time-consuming, less intraoperative blood loss and less venous resection, and therefore, may become a standard surgical approach to PD for BRPHC with the superior mesenteric vein-portal vein involvement but without superior mesenteric artery invasion.

Borderline resectable pancreatic cancer and vascular resections in the era of neoadjuvant therapy

While pancreatic cancer is still characterized by early systemic spread and poor outcomes,the treatment of this disease has changed significantly in recent years due to major advancements in systemic therapy and advanced surgical techniques.Broader use of effective neoadjuvant approaches combined with aggressive surgical operations within a multidisciplinary setting has improved outcomes.Borderline resectable pancreatic cancer is characterized by tumor vascular invasion,and is a setting where the combination of potent neoadjuvant chemotherapy and aggressive surgical methods,including vascular resections and reconstructions,shows its full potential.Hopefully,this will lead to improved local control and curative treatment in a number of patients with this aggressive malignancy.

Borderline resectable pancreatic cancer:Certainties and controversies

Borderline resectable(BR)pancreatic ductal adenocarcinoma(PDAC)is currently a well-recognized entity,characterized by some specific anatomic,biological and conditional features:It includes patients with a stage of disease intermediate between the resectable and the locally advanced ones.The term BR identifies a tumour with an aggressive biological behaviour,on which a neoadjuvant approach instead of an upfront surgery one should be preferred,in order to obtain a radical resection(R0)and to avoid an early recurrence after surgery.Even if during the last decades several studies on this topic have been published,some aspects of BR-PDAC still represent a matter of debate.The aim of this review is to critically analyse the available literature on this topic,particularly focusing on:The problem of the heterogeneity of definition of BR-PDAC adopted,leading to a misinterpretation of published data;its current management(neoadjuvant vs upfront surgery);which neoadjuvant regimen should be preferably adopted;the problem of radiological restaging and the determination of resectability after neoadjuvant therapy;the post-operative outcomes after surgery;and the role and efficacy of adjuvant treatment for resected patients that already underwent neoadjuvant therapy.

Neoadjuvant chemoradiation is associated with decreased lymph node ratio in borderline resectable pancreatic cancer:A propensity score matched analysis

Background:Lymph node ratio(LNR)and margin status have prognostic significance in pancreatic cancer.Herein we examined the pathologic and clinical outcomes in patients with borderline resectable pancreatic cancer(BRPC)following neoadjuvant therapy(NAT)and pancreaticoduodenectomy.Methods:Patients who underwent treatment between January 1,2012 and June 30,2017 were included.Sequential patients in the BRPC group were compared to a propensity score matched cohort of patients with radiographically resectable pancreatic cancer who underwent upfront surgical resection.The BRPC group was also compared to sequential patients with radiographically resectable pancreatic cancer who required vein resection(VR)during upfront surgery.Results:There were 50 patients in the BRPC group,50 patients in the matched control group,and 38 patients in the VR group.Negative margins(R0)were seen in 72%,64%,and 34%of the BRPC,control,and VR groups,respectively(P=0.521 for BRPC vs.control;P=0.002 for BRPC vs.VR),with 24%of the BRPC group requiring a vascular resection.Nodal stage was N0 in 64%,20%,and 18%of the BRPC,control,and VR groups,respectively(P<0.001 for BRPC vs.control or VR).When nodal status was stratified into four groups(N0,or LNR≤0.2,0.2–0.4,≥0.4),the BRPC group had a more favorable distribution(P<0.001).The median overall survival were 28.8,38.6,and 19.0 months for the BRPC,control,and VR groups,respectively(log-rank P=0.096).Conclusions:NAT in BRPC was associated with more R0 and N0 resections and lower LNR compared to patients undergoing upfront resection for resectable disease.

Borderline resectable for colorectal liver metastases:Present status and future perspective

Surgical resection for colorectal liver metastases(CRLM)may offer the best opportunity to improve prognosis.However,only about 20% of CRLM cases are indicated for resection at the time of diagnosis(initially resectable),and the remaining cases are treated as unresectable(initially unresectable).Thanks to recent remarkable developments in chemotherapy,interventional radiology,and surgical techniques,the resectability of CRLM is expanding.However,some metastases are technically resectable but oncologically questionable for upfront surgery.In pancreatic cancer,such cases are categorized as"borderline resectable",and their definition and treatment strategies are explicit.However,in CRLM,although various poor prognosis factors have been identified in previous reports,no clear definition or treatment strategy for borderline resectable has yet been established.Since the efficacy of hepatectomy for CRLM was reported in the 1970 s,multidisciplinary treatment for unresectable cases has improved resectability and prognosis,and clarifying the definition and treatment strategy of borderline resectable CRLM should yield further improvement in prognosis.This review outlines the present status and the future perspective for borderline resectable CRLM,based on previous studies.

The role of systemic therapy in borderline resectable and locally advanced pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma(PDAC)remains a deadly disease,even in patients whose cancer is localized and non-metastatic.Surgical resection provides the only option for cure,but long-term survival rates remain dismal.For patients with borderline resectable(BR)disease who undergo upfront resection,many patients are either too unwell for subsequent adjuvant systemic therapy,develop recurrence soon after,or are found to have unresectable disease intra-operatively.There is increasing evidence for a neoadjuvant approach,using more conventional multi-agent chemotherapy regimens,which have demonstrated higher activity in the metastatic setting compared to single agents.For patients with locally advanced(LA)disease,which is unresectable by current definitions,there is mounting evidence that effective neoadjuvant systemic therapy is able to convert some patients’disease to a resectable state,offering the potential for long-term survival and cure.Herein we present a review of key trials focusing on prospective,randomized studies to provide high-level evidence supporting a neoadjuvant approach to both BR and LA PDAC.However,many knowledge gaps exist,such as the optimal neoadjuvant multi-agent chemotherapy regimen,the role of radiotherapy,and the safety and efficacy of adding immunotherapy to chemo/radiation therapy.Future challenges in determining the optimal approach to patients with BR or LA PDAC include not only overcoming the inherent difficulties in conducting complex,multidisciplinary,multicentre randomized trials in patients with a high-morbidity and mortality disease,but also trying to standardize disease definitions,treatment regimens,and outcome measures.

Neoadjuvant therapy for resectable pancreatic cancer

The use of neoadjuvant therapies has played a major role for borderline resectable and locally advanced pancreatic cancers(PCs). For this group of patients, preoperative chemotherapy or chemoradiation has increased the likelihood of surgery with negative resection margins and overall survival. On the other hand, for patients with resectable PC, the main rationale for neoadjuvant therapy is that the overall survival with current strategies is unsatisfactory. There is a consensus that we need new treatments to improve the overall survival and quality of life of patients with PC. However, without strong scientific evidence supporting the theoretical advantages of neoadjuvant therapies, these potential benefits might turn out not to be worth the risk of tumors progression while waiting for surgery. The focus of this paper is to provide the readers an overview of the most recent evidence on this subject.

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.

Role of neoadjuvant therapy for nonmetastatic pancreatic cancer:Current evidence and future perspectives

Pancreatic adenocarcinoma(PDAC)is one of the most common and lethal human cancers worldwide.Surgery followed by adjuvant chemotherapy offers the best chance of a long-term survival for patients with PDAC,although only approximately 20%of the patients have resectable tumors when diagnosed.Neoadjuvant chemotherapy(NACT)is recommended for borderline resectable pancreatic cancer.Several studies have investigated the role of NACT in treating resectable tumors based on the recent advances in PDAC biology,as NACT provides the potential benefit of selecting patients with favorable tumor biology and controls potential micro-metastases in high-risk patients with resectable PDAC.In such challenging cases,new potential tools,such as ct-DNA and molecular targeted therapy,are emerging as novel therapeutic options that may improve old paradigms.This review aims to summarize the current evidence regarding the role of NACT in treating non-metastatic pancreatic cancer while focusing on future perspectives in light of recent evidence.

Advances in early diagnosis and therapy of pancreatic cancer

BACKGROUND: Pancreatic cancer remains a devastating disease with a 5-year survival rate of less than 5%. Recent advances in diagnostic methods and therapeutic approaches have increased the possibility of improving the existing poor prognosis. DATA SOURCES: English-language articles reporting early diagnosis and therapy of pancreatic cancer were searched from the MEDLINE and PubMed databases, Chinese-language articles were from CHKD (China Hospital Knowledge Database) RESULT: The current literature about pancreatic cancer was reviewed from three aspects: statistics, screening and early detection, and therapy. CONCLUSIONS: Early detection and screening of pancreatic cancer currently should be limited to high risk patients Surgical resection is the only curative approach available, with some recent improvement in outcomes. Gemcitabine has been a standard treatment during the last decade. Gemcitabine based combination treatment, especially combined with newer molecular targeted agents, is promising. The rationale for radiotherapy is controversial, but with the recent development of modern radiation delivery techniques, radiotherapy should be intensified. Patients with borderline pancreatic cancer could benefit from neoadjuvant therapy but more evidence is needed and the best neoadjuvant regimen is still to be determined.

Current and emerging therapeutic strategies in pancreatic cancer: Challenges and opportunities

Pancreatic carcinoma(PC)is one of the leading causes of cancer-related deaths worldwide.Despite early detection and advances in therapeutics,the prognosis remains dismal.The outcome and therapeutic approach are dependent on the stage of PC at the time of diagnosis.The standard of care is surgery,followed by adjuvant chemotherapy.The advent of newer drugs has changed the landscape of adjuvant therapy.Moreover,recent trials have highlighted the role of neoadjuvant therapy and chemoradiotherapy for resectable and borderline resectable PC.As we progress towards a better understanding of tumor biology,genetics,and microenvironment,novel therapeutic strategies and targeted agents are now on the horizon.We have described the current and emerging therapeutic strategies in PC.

Preoperative defining system for pancreatic head cancer considering surgical resection

AIM: To provide appropriate treatment, it is crucial to share the clinical status of pancreas head cancer among multidisciplinary treatment members.METHODS: A retrospective analysis of the medical records of 113 patients who underwent surgery for pancreas head cancer from January 2008 to December 2012 was performed. We developed preoperative defining system of pancreatic head cancer by describing &#x0201c;resectability - tumor location - vascular relationship - adjacent organ involvement - preoperative CA19-9 (initial bilirubin level) - vascular anomaly&#x0201d;. The oncologic correlations with this reporting system were evaluated.RESULTS: Among 113 patients, there were 75 patients (66.4%) with resectable, 34 patients (30.1%) with borderline resectable, and 4 patients (3.5%) with locally advanced pancreatic cancer. Mean disease-free survival was 24.8 mo (95%CI: 19.6-30.1) with a 5-year disease-free survival rate of 13.5%. Pretreatment tumor size &#x02265; 2.4 cm [Exp(B) = 3.608, 95%CI: 1.512-8.609, P = 0.044] and radiologic vascular invasion [Exp(B) = 5.553, 95%CI: 2.269-14.589, P = 0.002] were independent predictive factors for neoadjuvant treatment. Borderline resectability [Exp(B) = 0.222, P = 0.008], pancreatic head cancer involving the pancreatic neck [Exp(B) = 9.461, P = 0.001] and arterial invasion [Exp(B) = 6.208, P = 0.010], and adjusted CA19-9 &#x02265; 50 [Exp(B) = 1.972 P = 0.019] were identified as prognostic clinical factors to predict tumor recurrence.CONCLUSION: The suggested preoperative defining system can help with designing treatment plans and also predict oncologic outcomes.

Change in neoadjuvant chemotherapy could alter the prognosis of patients with pancreatic adenocarcinoma: A case report

BACKGROUND Neoadjuvant treatment has become a standard of care for borderline or locally advanced pancreatic cancer and is increasingly considered even for up-front resectable disease.The aim of this article is to present the case of a 62-year-old patient with locally advanced pancreatic adenocarcinoma who was successfully treated with gemcitabine plus nab-paclitaxel after the failure of the first line treatment.CASE SUMMARY Computerized tomography scan and magnetic resonance imaging demonstrated a nodular lesion of ill-defined limits in the body of the pancreas,measuring approximately 4.2 cm×2.7 cm,with an infiltrative aspect.The tumor had contact with the superior mesenteric vein,splenomesenteric junction and the proximal segment of the splenic artery,causing focal reduction of its lumens.Due to vascular involvement,neoadjuvant chemotherapy treatment with eight cycles of“folinic acid,5-fluorouracil,irinotecan and oxa-liplatine”(FOLFIRINOX)were performed.At the end of the cycles,surgery was performed,but the procedure was interrupted due to finding of lesions suspected of metastasis.Gemcitabine plus nab-paclitaxel was then successfully used for neoadjuvant treatment with subsequent R0 surgical resection.CONCLUSION Gemcitabine plus nab-paclitaxel may be effective as an alternative regimen when FOLFIRINOX fails as the first line of treatment,suggesting the need for further studies to identify which patients would benefit from each type of therapeutic approach.

Pancreatoduodenectomy with Simultaneous Venous Resection for Advanced Ductal Pancreatic Head Cancer:A Case Control Study

Introduction: Surgical resection is the treatment of choice for pancreatic ductal adenocarcinoma (PDA). However, in case of venous tumor in-volvement, carcinomas are classified as borderline resectable and their preferential therapy remains controversial. The purpose of this study is to analyze the effectiveness of the surgical approach with simultaneous venous resection regarding perioperative outcome and long-term survival. Patients and methods: All patients that underwent pancreatoduodenectomy (PD) for PDA at our institution between 02/2002 and 12/2016 were analyzed retrospectively. A matched-pair analysis between patients that underwent PD with simultaneous venous resection (PDVR) and standard PD was performed to compare perioperative parameters, survival and factors relevant to long-term survival. Results: The study included 142 patients: 71 underwent PDVR and 71 underwent standard PD. Venous tumor infiltration could histopathologically be confirmed in 21 patients (29.58%). PDVR wasn’t associated with a higher rate of postoperative complications (56.34% for both groups), severe postoperative complications (28.17% vs. 23.94%) and mortality (5.63% vs. 9.86%) compared to standard PD. Median overall survival of both groups was 17 months (95% CI 10.89 - 23.11), without statistical significance between the two groups (PD 22 months, 95% CI 16.02 - 27.99 vs. PDVR 16 months, 95% CI 9.96 - 22.04, p = 0.087). Parameters associated with overall survival were his-topathologically proven venous tumor infiltration, the lymph node status and the necessity of postoperative blood transfusions. Conclusion: PDVR is justified, because peri- and post-operative morbidity and mortality, as well as long-term survival, are comparable to standard PD. Even in case of postoperatively histopathologically confirmed venous tumor infiltration, patients benefit over palliative treatment.