The prognosis of pancreatic adenocarcinoma is dismal. Hence, advances in multidisciplinary treatment strategies, including surgery, are urgently needed. Early recurrence of distant organ metastases ...suggests that there are occult metastases even in cases with resectable disease. Several randomized controlled trials on adjuvant chemotherapy have been conducted to prolong survival after resection. CONKO-001 study was the first to demonstrate significant improvement in disease-free survival after surgery with gemcitabine administration. The JASPAC-01 study showed the superiority of adjuvant S1 over gemcitabine in survival after resection. Based on the results, adjuvant S1 therapy is the prescribed standard of care in Japan. Recently, the PRODIGE 24/CCTG PA.6 study showed that survival of patients treated with a modified FOLFIRINOX regimen as adjuvant therapy was significantly longer than those treated with adjuvant gemcitabine therapy. Although the evidence from these trials on adjuvant chemotherapy have been the gold-standard treatment for curatively resected and fully recovered patients, resectable disease at diagnosis is not the status, resected disease after curative resection. Currently, neoadjuvant therapy is considered to be a promising alternative to surgery for pancreatic cancer. Although there are many reports regarding neoadjuvant chemoradiotherapy, so far there has been no solid evidence proving the advantage of this strategy versus standard up-front surgery. Newly obtained results from the Prep-02/JSAP05 randomized phase II/III study, comparing neoadjuvant therapy with up-front surgery, revealed significant improvement in overall survival with neoadjuvant chemotherapy by intention-to-treat analysis. Thus, neoadjuvant intervention might become a new standard strategy in cases undergoing planned resection for pancreatic cancer.
The aim of the study was to evaluate the effect of neoadjuvant therapy on long-term survival in patients with resectable and borderline resectable pancreatic cancer. A meta-analysis was conducted ...using the reported randomized, controlled trials and retrospective studies using an intention-to-treat analysis to compare upfront surgery and neoadjuvant therapy in resectable or borderline resectable pancreatic cancer patients. Six comparative studies consisting of two randomized, controlled trials and four retrospective studies were included. The overall pooled hazard ratio was 0.66 (95% confidence interval: 0.50–0.87,
P
= 0.003), indicating that patients in the neoadjuvant group had better long-term survival than those in the upfront surgery group. However, considerable inter-study heterogeneity was observed (
I
2
= 62%). This meta-analysis focusing on comparative studies analyzed by intention-to-treat analysis showed that neoadjuvant therapy for resectable and borderline resectable pancreatic cancer tends to improve patients’ long-term outcomes. However, the evidence level remains too low for a firm conclusion. The well-designed, randomized, controlled trials now ongoing will provide the definite evidence needed in the future.
A randomized, controlled trial has begun to compare neoadjuvant chemotherapy using gemcitabine and S-1 with upfront surgery for patients planned resection of pancreatic cancer. Patients were enrolled ...after the diagnosis of resectable or borderline resectable by portal vein involvement pancreatic cancer with histological confirmation. They were randomly assigned to either neoadjuvant chemotherapy or upfront surgery. Adjuvant chemotherapy using S-1 was administered for 6 months to patients with curative resection who fully recovered within 10 weeks after surgery in both arms. The primary endpoint is overall survival; secondary endpoints include adverse events, resection rate, recurrence-free survival, residual tumor status, nodal metastases and tumor marker kinetics. The target sample size was required to be at least 163 (alpha-error 0.05; power 0.8) in both arms. A total of 360 patients were required after considering ineligible cases. This trial began in January 2013 and was registered with the UMIN Clinical Trials Registry (UMIN000009634).
Background
The morbidity rate after pancreaticoduodenectomy remains high. The objectives of this retrospective cohort study were to clarify the risk factors associated with serious morbidity ...(Clavien–Dindo classification grades IV–V), and create complication risk calculators using the Japanese National Clinical Database.
Methods
Between 2011 and 2012, data from 17,564 patients who underwent pancreaticoduodenectomy at 1,311 institutions in Japan were recorded in this database. The morbidity rate and associated risk factors were analyzed.
Results
The overall and serious morbidity rates were 41.6% and 4.5%, respectively. A pancreatic fistula (PF) with an International Study Group of Pancreatic Fistula (ISGPF) grade C was significantly associated with serious morbidity (P < 0.001). Twenty‐one variables were considered statistically significant predictors of serious complications, and 15 of them overlapped with those of a PF with ISGPF grade C. The predictors included age, sex, obesity, functional status, smoking status, the presence of a comorbidity, non‐pancreatic cancer, combined vascular resection, and several abnormal laboratory results. C‐indices of the risk models for serious morbidity and grade C PF were 0.708 and 0.700, respectively.
Conclusions
Preventing a PF grade C is important for decreasing the serious morbidity rate and these risk calculations contribute to adequate patient selection.
HighlightAoki and colleagues clarified the risk factors associated with serious morbidity (Clavien‐Dindo classification grades IV–V) and created risk calculators using a Japanese nationwide database of 17,564 patients after pancreaticoduodenectomy. Preventing pancreatic fistula grade C is important for reducing serious morbidity and these risk calculations contribute to more appropriate patient selection.
Although upfront surgery has been the gold standard for pancreatic adenocarcinoma that is planned for resection, it should be compared with the alternative strategy of neoadjuvant therapy. Despite ...the many reports of the efficacy of neoadjuvant therapy, most of them were not comparative. Recently Prep‐02/JSAP05 study clearly demonstrated the significant survival benefit of neoadjuvant chemotherapy over upfront surgery for pancreatic adenocarcinoma that is planned for resection. These findings opened a new chapter of neoadjuvant therapy. Ongoing trials are expected to confirm the evidence. This review summarizes the past, present, and future perspectives of neoadjuvant therapy and its optimization.
Recently, Prep‐02/JSAP05 study demonstrated the significant survival benefit of neoadjuvant chemotherapy over upfront surgery for pancreatic adenocarcinoma that is planned for resection. This review summarizes the past, present, and future perspectives of neoadjuvant and its optimization.
Background
Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is categorized into four distinct types: the gastric, intestinal, pancreatobiliary, and oncocytic. Each type is associated ...with specific clinicopathological features. We aimed to uncover the molecular mechanisms underlying the development of these types of IPMN.
Methods
We obtained 103 lesions of various types, including 49 gastric, 26 intestinal, 22 pancreatobiliary, and 6 oncocytic lesions, from 43 IPMNs, including 36 with multiple types. Comparative analysis was performed by targeted sequencing of 37 genes in different lesion types within each pancreas.
Results
Gastric-type low-grade lesions were observed in all 36 tumors with multiple types, with 245 mutations identified across all samples. The average number of mutations was significantly different between different lesion grades and types: 1.88 for low-grade lesions, 2.77 for high-grade lesions, and 2.38 for invasive lesions (
p
= 0.0067); and 1.96 for gastric-type lesion, 2.92 for intestinal-type lesion, 2.73 for pancreatobiliary-type lesion, and 2.17 for oncocytic-type lesion (
p
= 0.0163). Tracing of mutations between lesions containing multiple types in the same pancreas suggested three developmental pathways, denoted as “progressive”, “divergent”, and “independent”. The progressive and divergent pathways indicate an ancestral lesion that was mostly gastric-type and low-grade may progress or diversify into lesions of other types and/or higher grades. The independent pathway suggests that some high-grade lesions of any type may develop independently.
Conclusion
These findings suggest that gastric-type low-grade lesions have a risk of progression into high-grade lesions of other types. Therefore, low-grade gastric-type IPMNs should be under constant surveillance.
Purpose
We aimed to clarify the prognostic impact of postoperative circulating tumor DNA (ctDNA) shortly after pancreatectomy in patients with pancreatic ductal adenocarcinoma (PDAC).
Methods
...Preoperative and paired postoperative blood samples were obtained from 66 patients in patients with PDAC. Cell‐free DNA was extracted from the plasma, and KRAS mutations, as a benchmark of ctDNA, were examined using droplet digital PCR. Disease‐free survival (DFS) and overall survival (OS) were compared between patients with presence and absence of ctDNA.
Results
In univariate analysis, patients with detectable postoperative ctDNA showed worse survival than those with undetectable in both DFS (P = .034) and OS (P = .022). Multivariate analysis also revealed that the presence of postoperative ctDNA was an independent risk factor for recurrence (hazard ratio: 2.677, P = .011). In contrast, preoperative ctDNA detection did not affect long‐term outcomes. These trends persisted in 34 patients with resectable PDAC who underwent resection after neoadjuvant chemotherapy. Patients with detectable postoperative ctDNA were more prone to developing hepatic recurrence than those with undetectable postoperative ctDNA (P = .039).
Conclusion
Postoperative ctDNA, as a minimal residual marker, can be useful for predicting the risk of recurrence in patients with PDAC even after curative resection.
Hata et al. evaluated the ctDNA prevalence in preoperative and paired postoperative blood samples obtained from 66 patients with PDAC who underwent resection. Patients with detectable postoperative ctDNA showed worse survival than those with undetectable in both disease‐free survival and overall survival. In contrast, preoperative ctDNA detection did not affect long‐term outcomes.
Background
Neoadjuvant chemotherapy (NAC) represents a promising alternative to pancreatic ductal adenocarcinoma (PDAC) planned resection, but the survival impact remains undefined. To assess the ...feasibility and survival outcomes of NAC with gemcitabine and S1 (GS) for PDAC planned resection by prospective study.
Methods
Patients with resectable or borderline resectable PDAC received 2 cycles of NAC-GS and were offered curative resection followed by gemcitabine adjuvant. The primary endpoint was 2-year overall survival (OS). Adverse events during NAC, radiological and tumor marker responses, resection rate, and surgical safety were evaluated as secondary endpoints (UMIN000004148).
Results
We enrolled 104 patients between 2010 and 2012, with 101 patients treated using NAC-GS as the full analysis set (FAS). Of the 101 patients, 88% received the planned 2 cycles of NAC. Grade 3 neutropenia was common (35%). Radiological partial response and decreased carbohydrate antigen 19-9 concentration (> 50% decrease) were noted in 13% and 41%, respectively. R0/1 resections with M0 were performed in 65 patients without surgical mortality. Of the 65 patients, 44 received planned gemcitabine adjuvant for 6 months as the on-protocol cohort. The primary endpoint for the 2-year OS rate was 55.9% in the FAS (
n
= 101) and 74.6% in the on-protocol cohort (
n
= 44).
Conclusions
NAC-GS was feasible and actively prolonged survival following PDAC planned resection. Randomized control trials are needed to further clarify the survival benefit of NAC-GS in addition to surgery followed by adjuvant therapy.
PDF
