Neoadjuvant treatment for resectable pancreatic adenocarcinoma

Pancreatic adenocarcinoma is the fourth leading cause of cancer mortality in the United States in both men and women, with a 5-year survival rate of less than 5%. Surgical resection remains the only curative treatment, but most patients develop systemic recurrence within 2 years of surgery. Adjuvant treatment with chemotherapy or chemoradiotherapy has been shown to improve overall survival, but the delivery of treatment remains problematic with up to 50% of patients not receiving postoperative treatment. Neoadjuvant therapy can provide benefits of eradication of micrometastasis and improved delivery of intended treatment. We have reviewed the findings from completed neoadjuvant clinical trials, and discussed the ongoing studies. Combinational cytotoxic chemotherapy such as fluorouracil, leucovorin, irinotecan, and oxaliplatin and gemcitabine plus nanoparticle albumin-bound(nab)-paclitaxel, active in the metastatic setting, are being studied in the neoadjuvant setting. In addition, novel targeted agents such as inhibitor of immune checkpoint are incorporated with cytotoxic chemotherapy in early-phase clinical trial. Furthermore we have explored the utility of biomarkers which can personalize treatment and select patients for target-driven therapy to improve treatment outcome. The treatment of resectable pancreatic adenocarcinoma requires multidisciplinary approach and novel strategies including innovative trials to make progress.

A Systematic Review of Neoadjuvant Therapy Compared to the “Resection First” Approach for Patients with Borderline Resectable Pancreatic Adenocarcinoma

Background: Survival for patients with pancreatic adenocarcinoma continues to be poor. Patients with pancreatic adenocarcinoma that is deemed borderline resectable have imaging that shows disease involvement of the portal vein and/or superior mesenteric vein that is amenable to reconstruction or abutment (≤180 degrees) of the superior mesenteric artery. The best initial treatment for patients with borderline resectable pancreatic adenocarcinoma has yet to be determined. Proponents of neoadjuvant therapy purport its utility for patients with borderline resectable pancreatic adenocarcinoma with the intention of increasing the likelihood of a microscopically negative (R0) margin, but the consequences of this approach are not established. This study was undertaken to systematically review the outcomes for patients with borderline resectable pancreatic adenocarcinoma to compare neoadjuvant therapy to a “resection first” approach. Methods: A MEDLINE/PubMed search was undertaken to find all studies regarding patients who underwent neoadjuvant therapy for patients with borderline resectable pancreatic adenocarcinoma. Results: A total of 112 studies were found regarding borderline resectable pancreatic cancer. Fourteen studies contained cohorts of patients with borderline resectable pancreatic adenocarcinoma who received neoadjuvant therapy (n = 471 patients) or a resection-first approach (n = 76 patients). Resection after neoadjuvant therapy was undertaken for 233 (49%) patients. Neoadjuvant therapy followed by an R0 resection occurred for 42% of patients. For patients who underwent resection first, 71% (54/76) had an R0 margin. Conclusion: Patients with borderline resectable pancreatic adenocarcinoma were more often found to undergo neoadjuvant therapy than a “resection first” approach in the available literature. Although neoadjuvant therapy portends a high rate of R0 resections, less than half of the patients who undergo neoadjuvant therapy for borderline resectable pancreatic adenocarcinoma undergo resection. Patients who undergo “resection first” for borderline resectable pancreatic adenocarcinoma have an increased chance for a resection and an R0 margin compared to patients who undergo neoadjuvant therapy for borderline pancreatic adenocarcinoma.

A contemporary evidence basis for neoadjuvant chemotherapy in upfront resectable pancreatic adenocarcinoma:a systematic review of the literature

Pancreatic ductal adenocarcinoma(PDAC)is an aggressive cancer with poor survival.Local control through surgical resection paired with radiotherapy and chemotherapy comprise the primary tenets of treatment.Debate exists regarding the timing of treatment and ordering of systemic therapy and resection in the management of early stage disease.The goal of this study was to review the literature and describe the contemporary evidence basis for the role of neoadjuvant therapy(NAT)in the setting of upfront resectable(UP-R)PDAC.Five databases were searched in parallel to identify relevant original articles investigating neoadjuvant therapy where at least 1 study arm contained UP-R PDAC;studies with only borderline resectable or locally advanced disease were excluded.Due to the diversity in NAT regimens and study design between trials,qualitative analyses were performed to investigate patient selection,impact on perioperative and survival outcomes,safety,and cost effectiveness.Thirty-five studies met inclusion criteria,of which 24 unique trials are discussed here in detail.These studies included those trials using single agents as well as more recent trials comparing modern multiagent therapies,and several large database analyses.Overall the data suggest that NAT is safe,may confer survival benefit for appropriately selected patients,is cost effective,and is an appropriate approach for UP-R PDAC.Nevertheless,the risk for disease progression during upfront medical therapy,requires appropriate patient identification and close monitoring,and emphasizes the need for further discovery of more effective chemotherapeutics,useful biomarkers or molecular profiles,and additional prospective comparative studies.

Effect of multiple-phase regional intra-arterial infusion chemotherapy on patients with resectable pancreatic head adenocarcinoma

Background Regional intra-arterial infusion chemotherapy （RIAC） has been more valuable to improve prognosis and quality of life of patients with inoperable pancreatic adenocarcinomas, and adjuvant RIAC plays an important role in prolonging survival and reducing risk of liver metastasis after radical resection of pancreatic cancer, but the effect of preoperative or multiple-phase RIAC （preoperative combined with postoperative RIAC） for resectable pancreatic cancers has not been investigated. In this prospective study, the effect of multiple-phase RIAC for patients with resectable pancreatic head adenocarcinoma was evaluated, and its safety and validity comparing with postoperative RIAC were also assessed. Methods Patients with resectable pancreatic head cancer were randomly assigned to two groups. Patients in group A （n=-50） were treated with new therapeutic mode of extended pancreaticoduodenectomy combined with multiple-phase RIAC, and those in group B （n=-50） were treated with extended pancreaticoduodenectomy combined with postoperative RIAC in the same period. The feasibility, compliance and efficiency of the new therapeutic mode were evaluated by tumor size, serum tumor markers, clinical benefit response （CBR）, surgical complications, mortality and toxicity of RIAC. The disease-free survival time, median survival time, incidence of liver metastasis, survival rate at 1, 2, 3 and 5 years were also observed. Life curves were generated by the Kaplan-Meier method. Results The pain relief rate and CBR in group A was 80% and 84% respectively. Serum tumor markers decreased obviously and tumors size decreased in 26% of patients after preoperative RIAC in group A. No more surgical complications, mortality or severe systemic side effects were observed in group A compared with group B. The incidence of liver metastasis in group A was 34% which was lower than 50% in group B. The disease-free survival time and median survival time in group A were 15.5 months and 18 months respectively. The 1-, 2-, 3- and 5-year survival rates were 54.87%, 34.94%, 24.51% and 12.25% respectively. There was no significant difference of survival time or survival rates between two groups. Conclusions Multiple-phase RIAC is effective in combined therapy of resectable pancreatic head carcinomas by enhancing inhibition of tumor growth and reduction of liver metastasis, without negative effect on patients＇ safety or surgical procedure.

Neoadjuvant treatment of pancreatic ductal adenocarcinoma:Whom,when and how

Pancreatic ductal adenocarcinoma(PDAC),which is notorious for its aggressiveness and poor prognosis,remains an area of great unmet medical need,with a 5-year survival rate of 10%-the lowest of all solid tumours.At diagnosis,only 20%of patients have resectable pancreatic cancer(RPC)or borderline RPC(BRPC)disease,while 80%of patients have unresectable tumours that are locally advanced pancreatic cancer(LAPC)or have distant metastases.Nearly 60%of patients who undergo upfront surgery for RPC are unable to receive adequate adjuvant chemotherapy(CHT)because of postoperative complications and early cancer recurrence.An important paradigm shift to achieve better outcomes has been the sequence of therapy,with neoadjuvant CHT preceding surgery.Three surgical stages have emerged for the preoperative assessment of nonmetastatic pancreatic cancers:RPC,BRPC,and LAPC.The main goal of neoadjuvant treatment(NAT)is to improve postoperative outcomes through enhanced selection of candidates for curative-intent surgery by identifying patients with aggressive or metastatic disease during initial CHT,reducing tumour volume before surgery to improve the rate of margin-negative resection(R0 resection,a microscopic margin-negative resection),reducing the rate of positive lymph node occurrence at surgery,providing early treatment of occult micrometastatic disease,and assessing tumour chemosensitivity and tolerance to treatment as potential surgical criteria.In this editorial,we summarize evidence concerning NAT of PDAC,providing insights into future practice and study design.Future research is needed to establish predictive biomarkers,measures of therapeutic response,and multidisciplinary stra tegies to improve patient-centered outcomes.

Efficacy and safety of laparoscopic radical resection following neoadjuvant therapy for pancreatic ductal adenocarcinoma:A retrospective study

BACKGROUND Multiple studies have demonstrated that neoadjuvant chemotherapy(NACT) can prolong the overall survival of pancreatic ductal adenocarcinoma(PDAC) patients. However, most studies have focused on open surgery following NACT.AIM To investigate the efficacy and safety of laparoscopic radical resection following NACT for PDAC.METHODS We retrospectively analyzed the clinical data of 15 patients with pathologically confirmed PDAC who received NACT followed by laparoscopic radical surgery in our hospital from December 2019 to April 2022. All patients underwent abdominal contrast-enhanced computed tomography(CT) and positron emission tomography-CT before surgery to accurately assess tumor stage and exclude distant metastasis.RESULTS All 15 patients with pancreatic cancer were successfully converted to surgical resection after NACT, including 8 patients with pancreatic head cancer and 7 patients with pancreatic body and tail cancer. Among them, 13 patients received the nab-paclitaxel plus gemcitabine regimen(gemcitabine 1000 mg/m^(2) plus nabpaclitaxel 125 mg/m^(2) on days 1, 8, and 15 every 4 wk) and 2 patients received the modified FOLFIRINOX regimen(intravenous oxaliplatin 68 mg/m^(2), irinotecan 135 mg/m^(2), and leucovorin 400 mg/m^(2) on day 1 and fluorouracil 400 mg/m^(2) on day 1, followed by 46-h continuous infusion of fluorouracil 2400 mg/m^(2)). After each treatment cycle, abdominal CT, tumor markers, and circulating tumor cell counts were reviewed to evaluate the treatment efficacy. All 15 patients achieved partial remission. The surgical procedures included laparoscopic pancreaticoduodenectomy(LPD, n = 8) and laparoscopic radical antegrade modular pancreatosplenectomy(L-RAMPS, n = 7). None of them were converted to a laparotomy. One patient with pancreatic head carcinoma was found to have portal vein involvement during the operation, and LPD combined with vascular resection and reconstruction was performed. The amount of blood loss and operation times of L-RAMPS vs LPD were 435.71 ± 32.37 m L vs 343.75 ± 145.01 m L and 272.52 ± 49.14 min vs 444.38 ± 68.63 min, respectively. The number of dissected lymph nodes was 16.87 ± 4.10, and 3 patients had positive lymph nodes. One patient developed grade B postoperative pancreatic fistula(POPF) after LRAMPS, and one patient experienced jaundice after LPD. None of the patients died after surgery. As of April 2022, progressive disease was noted in 4 patients, 2 patients had liver metastasis, and one had both liver metastasis and lymph node metastasis and died during the follow-up period.CONCLUSION Laparoscopic radical resection of PDAC after NACT is safe and effective if it is performed by a surgeon with rich experience in LPD and in a large center of pancreatic surgery.

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.

Response evaluation following neoadjuvant treatment of pancreatic cancer patients

Pancreatic ductal adenocarcinoma(PDAC) is one of the most aggressive human neoplastic entities,with a very poor prognosis characterized by a high mortality rate and short survival.This is due both to its aggressive biological behaviour and the high incidence of locally advanced stages at the time of the initial diagnosis.The limits of resectability and the role of neoadjuvant(radio) chemotherapy for PDAC management are still unclear.A recently published article by Kats et al compared the radiological,surgical and histopathological results of 129 patients with borderline resectable tumors undergoing neoadjuvant treatment followed by surgery.Although post-neoadjuvant treatment imaging implied a low response rate,a high rate of complete resections was achieved.This seems to confirm that,though radiology has made a significant progress in defining locally advanced PDAC,there is place for further improvement.In particular,the differentiation between radiotherapy-induced scarring/fibrosis and cancer-associated desmoplasia remains a clinical/radiological challenge.Though selection of patients with occult systemic disease is possible with neoadjuvant treatment,downstaging does not seem to occur frequently.Thus,development of novel,more aggressive(radio) chemotherapy regimens is required to improve prognosis of patients with locally unresectable but not systemically micro-metastasized tumors.

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.

Neoadjuvant therapy for resectable pancreatic cancer:a narrative review

The use of neoadjuvant therapy(NAT)for pancreatic ductal adenocarcinoma remains controversial and limited.Therefore,this literature review aimed to assess the feasibility,safety,and efficacy of this treatment.A database search of peer-reviewed articles published in English between January 1990 and June 2021 in PubMed,MEDLINE,and the Web of Science was performed.Original articles,review articles,and meta-analyses relevant to the topic were selected.We found 2 to 4 cycles with FOLFIRINOX,gemcitabine plus nab-paclitaxel,gemcitabine plus S-1,or gemcitabine alone were the most acceptable treatments.Considering the risk of adverse events and cancer progression,NAT is considered safe and tolerable,with a comparable resection rate.Although NAT can result in moderate tumor responses and some extent of local control(improvement of complete resection rate and negative lymph node metastases),no obvious survival benefit is observed.To date,the survival benefits of NAT for resectable pancreatic ductal adenocarcinoma have been very limited.It is too early to say that NAT is the best treatment option for resectable pancreatic cancer.

Systemic therapy without radiation may be appropriate as neoadjuvant therapy for localized pancreas cancer

Background:The utility of neoadjuvant treatment for resectable pancreas cancer is yet to be determined,but has commonly included chemoradiation.We evaluated outcomes in patients with radiographically resectable pancreatic adenocarcinoma treated with neoadjuvant chemotherapy without chemoradiation.Methods:A retrospective review of patients in our institutional pancreatic cancer registry was performed,which identified 36 patients who received neoadjuvant chemotherapy alone for resectable pancreatic adenocarcinoma between 2012 and 2016.Results:Median age at diagnosis was 66.3 years.Chemotherapy regimens included gemcitabine(n=17),gemcitabine/nab-paclitaxel(n=8),or 5-FU/leucovorin/irinotecan/oxaliplatin(FOLFIRINOX)(n=11).Surgical resection was performed in 69%of patients(n=25),with an R0 resection rate of 92%(n=23 patients).During chemotherapy,distant disease became apparent in 19%of patients(n=7),while no patients had evidence of local progression.Resection rates were similar between chemotherapy regimens(single agent=59%,multiple agent=79%).Median overall survival for all patients who received neoadjuvant chemotherapy was 30.3 and 34.4 months for those who underwent surgical resection.There was no difference in median survival for patients treated with gemcitabine(31.3 months)or multi-agent chemotherapy(29.7 months).Conclusions:A short course of neoadjuvant chemotherapy without chemoradiation may improve patient selection prior to surgical resection for pancreas cancer.Further,local disease progression did not limit surgical resection in this small series.

临界可切除胰腺癌新辅助治疗研究进展

临界可切除胰腺导管腺癌(BR-PDAC)约占初诊胰腺癌患者的20%,介于可切除与不可切除之间,具有高度的解剖学、生物学、身体条件等方面的异质性。侵袭性的生物学行为决定这部分患者应优先考虑新辅助治疗而不是直接手术,从而达到R0切除避免术后的早期复发。然而,这一治疗模式仍然存在争议。根据这一主题的最新研究,本文从BR-PDAC的定义、新辅助治疗选择与评估、新辅助治疗后手术结果、新辅助治疗后辅助治疗的疗效等方面进行综述。

系统免疫炎症指数与接受新辅助化疗胰腺导管腺癌患者预后的关系

目的探讨新辅助化疗后系统免疫炎症指数(systemic immune-inflammation index,SII)对胰腺导管腺癌(pancreatic ductal adenocarcinoma,PDAC)预后评估的价值。方法回顾性分析2013年1月至2016年12月在盘锦辽油宝石花医院行胰腺切除术的PDAC患者的临床资料。新辅助化疗后检测SII,依据ROC曲线确定SII最佳临界值(885)分为SII>885组(n=37)和SII≤885组(n=58),采用Cox回归评估SII与PDAC患者术后生存的关系。结果SII与肿瘤大小、胆道引流、术前CA19-9水平有关(P<0.05)。SII≤885组的3年生存率高于SII>885(43.1%vs 18.9%,P=0.015)。多因素Cox回归显示,肿瘤大小>3 cm(HR=1.367,95%CI:1.227~2.215,P=0.031)、CA19-9>37 IU/mL(HR=1.292,95%CI:1.132~1.931,P=0.011)及SII>885(HR=1.451,95%CI:1.327~2.431,P=0.021)是影响PDAC患者术后生存的独立危险因素。结论新辅助化疗后SII高的PDAC患者预后较差且SII>885提示PDAC患者预后不良。

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.