Meta-analysis of the impact of neoadjuvant therapy on patterns of recurrence in pancreatic ductal adenocarcinoma.
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ABSTRACT:
SUBMITTER: Schorn S
PROVIDER: S-EPMC5989995 | biostudies-literature | 2018 Apr
REPOSITORIES: biostudies-literature
Publications
Meta-analysis of the impact of neoadjuvant therapy on patterns of recurrence in pancreatic ductal adenocarcinoma.
Schorn S S Demir I E IE Samm N N Scheufele F F Calavrezos L L Sargut M M Schirren R M RM Friess H H Ceyhan G O GO
BJS open 20180330 2
<h4>Background</h4>Neoadjuvant therapy may increase the rate of radical tumour resection in patients with pancreatic cancer. Its impact on tumour recurrence has not been investigated fully. This study aimed to assess the impact of neoadjuvant therapy on patterns of recurrence.<h4>Methods</h4>A systematic review was performed of articles identified through the PubMed, Scopus, Embase, Ovid and Google Scholar databases that analysed the relationship between neoadjuvant therapy and recurrence publis ...[more]
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Project description:Neoadjuvant therapy (NAT) represents a paradigm shift in the management of patients with pancreatic ductal adenocarcinoma (PDAC) with perceived benefits including a higher R0 rate. However, it is unclear whether NAT affects the sites and patterns of recurrence after surgery. This review seeks to compare sites and patterns of recurrence after resection between patients undergoing upfront surgery (US) or after NAT. The EMBASE, SCOPUS, PubMed, and Cochrane library databases were systematically searched to identify eligible studies that compare recurrence patterns between patients who had NAT (followed by resection) with those that had US. The primary outcome included site-specific recurrence. 26 articles were identified including 4986 patients who underwent resection. Borderline resectable pancreatic cancer (BRPC, 47% 1074/2264) was the most common, followed by resectable pancreatic cancer (RPC 42%, 949/2264). The weighted overall recurrence rates were lower among the NAT group, 63.4% vs. 74% (US) (OR 0.67 (CI 0.52-0.87), p = 0.006). The overall weighted locoregional recurrence rate was lower amongst patients who received NAT when compared to US (12% vs 27% OR 0.39 (CI 0.22-0.70), p = 0.004). In BRPC, locoregional recurrence rates improved with NAT (NAT 25.8% US 37.7% OR 0.62 (CI 0.44-0.87), p = 0.007). NAT was associated with a lower weighted liver recurrence rate (NAT 19.4% US 30.1% OR 0.55 (CI 0.34-0.89), p = 0.023). Lung and peritoneal recurrence rates did not differ between NAT and US cohorts (p = 0.705 and p = 0.549 respectively). NAT was associated with a significantly longer weighted mean time to first recurrence 18.8 months compared to US (15.7 months) (OR 0.18 (CI 0.05-0.32), p = 0.015). NAT was associated with lower overall recurrence rate and improved locoregional disease control particularly for those with BRPC. Although the burden of liver metastases was less, there was no overall effect upon distant metastatic disease.
| S-EPMC7408905 | biostudies-literature
Project description:The incidence of pancreatic ductal adenocarcinoma (PDAC) has been on the rise in recent years; however, its clinical diagnosis and treatment remain challenging. Although surgical resection remains the only chance for long-term patient survival, the likelihood of initial resectability is no higher than 20%. Neoadjuvant therapy (NAT) in PDAC aims to transform the proportion of inoperable PDACs into operable cases and reduce the likelihood of recurrence to improve overall survival. Ongoing phase 3 clinical trial aims to validate the role of NAT in PDAC therapy, including prolongation of survival, increased R0 resection, and a higher proportion of negative lymph nodes. Controversies surrounding the role of NAT in PDAC treatment include applicability to different stages of PDAC, chemotherapy regimens, radiation, duration of treatment, and assessment of effect. This review aims to summarize the current progress and controversies of NAT in PDAC.
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Project description:Pancreatic ductal adenocarcinoma (PDAC) is becoming increasingly more common. Treatment for PDAC is dependent not only on stage at diagnosis, but complex anatomical relationships. Recently, the therapeutic approach to this disease has shifted from upfront surgery for technically resectable lesions to a neoadjuvant therapy first approach. Selecting an appropriate regimen and determining treatment response is crucial for optimal oncologic outcome, especially since radiographic imaging has proven unreliable in this setting. Tumor biomarkers have the potential to play a key role in treatment planning, treatment monitoring, and surveillance as an adjunct laboratory test. In this review, we will discuss common chemotherapeutic options, mechanisms of resistance, and potential biomarkers for PDAC. The aim of this paper is to present currently available biomarkers for PDAC and to discuss how these markers may be affected by neoadjuvant chemotherapy treatment. Understanding current chemotherapy regiments and mechanism of resistance can help us understand which markers may be most affected and why; therefore, determining to what ability we can use them as a marker for treatment progression, prognosis, or potential relapse.
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| S-EPMC8971157 | biostudies-literature
Project description:BackgroundNeoadjuvant treatment has proven beneficial for many gastrointestinal (GI) malignancies, but no phase III trials have been completed examining this approach in pancreatic cancer. This meta-analysis examines the best available phase II trials using neoadjuvant treatment for resectable and borderline/unresectable pancreatic adenocarcinoma.MethodsPhase II trials were identified using a MEDLINE search, and the Cochrane Central Register of Controlled Trials from 1960 to July 2010. Patients were divided into 2 groups: Patients with initially resectable tumors (group A), and patients with borderline/unresectable tumors (group B). Primary outcome measures were rate of resection and survival. Pooled proportions and 95% confidence intervals (CIs) were calculated using random-effects or fixed-effects models based on the heterogeneity of included studies.ResultsA total of 14 phase II clinical trials including 536 patients were analyzed. After treatment, resectability was 65.8% (95% CI, 55.4-75.6%) compared with 31.6% in group B (95% CI, 14.0-52.5%). A partial response was observed in patients with borderline/unresectable tumors; 31.8 (95% CI, 24.2-39.8%) in group B and 9.5% (95% CI, 2.9-19.4%) in group A (P = .003). Progressive disease was seen in 17.0% (95% CI, 11.9-22.7) of patients in group A versus 21.8% (95% CI, 10.1-36.5%) in group B (P = .006). Median survival in resected patients was 23 months for group A and 22 months for group B.ConclusionNeoadjuvant treatment seems to have some activity in patients with borderline/unresectable pancreatic adenocarcinoma. Nearly one third of tumors initially deemed marginal for operative intervention were able to be ultimately resected after treatment. Until more effective targeted chemotherapeutics are developed, the only group of patients with pancreatic cancer that may benefit from neoadjuvant treatment are those with locally advanced disease.
| S-EPMC3164966 | biostudies-literature
Project description:BackgroundHerein, we investigate the relationship between pancreatic stem cell markers (PCSC markers), CD44, and epithelial-specific antigen (ESA), tumor stroma, and the impact on recurrence outcomes in pancreatic ductal adenocarcinoma (PDAC) patients.MethodsPDAC patients who underwent surgical resection between 01/2012-06/2014 were identified. CD44 and ESA expression was assessed by immunohistochemistry. Stroma was classified as loose, moderate, and dense based on fibroblast content. Overall survival (OS) and relapse-free survival (RFS) were estimated using the Kaplan-Meier method and compared between subgroups by log-rank test. The association between PCSC markers and stroma type was assessed by Fisher's exact test.ResultsN = 93 PDAC patients were identified. The number of PDAC patients with dense, moderate density, and loose stroma was 11 (12%), 51 (54%), and 31 (33%) respectively. PDAC with CD44+/ESA- had highest rate of loose stroma (63%) followed by PDAC CD44+/ESA+ (50%), PDAC CD44-/ESA+ (35%), CD44-/ESA- (9%) (p = 0.0033). Conversely, lack of CD44 and ESA expression was associated with the highest rate of moderate and dense stroma (91% p = 0.0033). No local recurrence was observed in patients with dense stroma and 9 had distant recurrence. The highest rate of cumulative local recurrence was observed in patients with loose stroma. No statistically significant difference in RFS and OS was observed among subgroups (P = 0.089).ConclusionsThese data indicate PCSCs may have an important role in stroma differentiation in PDAC. Our results further suggest that tumor stroma may influence the recurrence pattern in PDAC patients.
| S-EPMC8034174 | biostudies-literature
Project description:PurposeWe investigated whether organoids can be generated from resected tumors of patients who received eight cycles of neoadjuvant FOLFIRINOX chemotherapy before surgery, and evaluated the sensitivity/resistance of these surviving cancer cells to cancer therapy.Experimental designWe generated a library of 10 pancreatic ductal adenocarcinoma (PDAC) organoid lines: five each from treatment-naïve and FOLFIRINOX-treated patients. We first assessed the histologic, genetic, and transcriptional characteristics of the organoids and their matched primary PDAC tissue. Next, the organoids' response to treatment with single agents-5-FU, irinotecan, and oxaliplatin-of the FOLFIRINOX regimen as well as combined regimen was evaluated. Finally, global mRNA-seq analyses were performed to identify FOLFIRINOX resistance pathways.ResultsAll 10 patient-derived PDAC organoids recapitulate histologic, genetic, and transcriptional characteristics of their primary tumor tissue. Neoadjuvant FOLFIRINOX-treated organoids display resistance to FOLFIRINOX (5/5), irinotecan (5/5), and oxaliplatin (4/5) when compared with treatment-naïve organoids (FOLFIRINOX: 1/5, irinotecan: 2/5, oxaliplatin: 0/5). 5-Fluorouracil treatment responses between naïve and treated organoids were similar. Comparative global transcriptome analysis of treatment-naïve and FOLFIRINOX samples-in both organoids and corresponding matched tumor tissues-uncovered modulated pathways mainly involved in genomic instability, energy metabolism, and innate immune system.ConclusionsResistance development in neoadjuvant FOLFIRINOX organoids, recapitulating their primary tumor resistance, suggests continuation of FOLFIRINOX therapy as an adjuvant treatment may not be advantageous for these patients. Gene-expression profiles of PDAC organoids identify targetable pathways involved in chemoresistance development upon neoadjuvant FOLFIRINOX treatment, thus opening up combination therapy possibilities.
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Project description:BackgroundNeoadjuvant folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) and chemoradiation have been used to downstage borderline and locally advanced pancreatic ductal adenocarcinoma (PDAC). Whether neoadjuvant therapy-induced tumor immune response contributes to the improved survival is unknown. Therefore, we evaluated whether neoadjuvant therapy induces an immune response towards PDAC.MethodsClinicopathological variables were collected for surgically resected PDACs at the Massachusetts General Hospital (1998-2016). Neoadjuvant regimens included FOLFIRINOX with or without chemoradiation, proton chemoradiation (25 Gy), photon chemoradiation (50.4 Gy), or no neoadjuvant therapy. Human leukocyte antigen (HLA) class I and II expression and immune cell infiltration (CD4+, FoxP3+, CD8+, granzyme B+ cells, and M2 macrophages) were analyzed immunohistochemically and correlated with clinicopathologic variables. The antitumor immune response was compared among neoadjuvant therapy regimens. All statistical tests were 2-sided.ResultsTwo hundred forty-eight PDAC patients were included. The median age was 64 years and 50.0% were female. HLA-A defects were less frequent in the FOLFIRINOX cohort (P = .006). HLA class II expression was lowest in photon and highest in proton patients (P = .02). The FOLFIRINOX cohort exhibited the densest CD8+ cell infiltration (P < .001). FOLFIRINOX and proton patients had the highest CD4+ and lowest T regulatory (FoxP3+) cell density, respectively. M2 macrophage density was statistically significantly higher in the treatment-naïve group (P < .001) in which dense M2 macrophage infiltration was an independent predictor of poor overall survival.ConclusionsNeoadjuvant FOLFIRINOX with or without chemoradiation may induce immunologically relevant changes in the tumor microenvironment. It may reduce HLA-A defects, increase CD8+ cell density, and decrease T regulatory cell and M2 macrophage density. Therefore, neoadjuvant FOLFIRINOX therapy may benefit from combinations with checkpoint inhibitors, which can enhance patients' antitumor immune response.
| S-EPMC7850539 | biostudies-literature
Project description:Background: Non-randomized studies have investigated multi-agent gemcitabine-based neo-adjuvant therapies (GEM-NAT) in borderline resectable pancreatic ductal adenocarcinoma (BR-PDAC). Treatment sequencing and specific elements of neoadjuvant treatment are still under investigation. The present meta-analysis aims to assess the effectiveness of GEM-NAT on overall survival (OS) in BR-PDAC. Patients and Methods: A meta-analysis of individual participant data (IPD) on GEM-NAT for BR-PDAC were performed. The primary outcome was OS after treatment with GEM-based chemotherapy. In the Individual Patient Data analysis data were reappraised and confirmed as BR-PDAC on provided radiological data. Results: Six studies investigating GEM-NAT were included in the IPD metanalysis. The IPD metanalysis was conducted on 271 patients who received GEM-NAT. Pooled median patient-level OS was 22.2 months (95%CI 19.1-25.2). R0 rates ranged between 81 and 95% (I 2 = 0%, p = 0.64), respectively. Median OS was 27.8 months (95%CI 23.9-31.6) in the patients who received NAT-GEM followed by resection compared to 15.4 months (95%CI 12.3-18.4) for NAT-GEM without resection and 13.0 months (95%CI 7.4-18.5) in the group of patients who received upfront surgery (p < 0.0001). R0 rates ranged between 81 and 95% (I 2 = 0%, p = 0.64), respectively. Overall survival in the R0 group was 29.3 months (95% CI 24.3-34.2) vs. 16.2 months (95% CI 7·9-24.5) in the R1 group (p = 0·001). Conclusions: The present study is the first meta-analysis combining IPD from a number of international centers with BR-PDAC in a cohort that underwent multi-agent gemcitabine neoadjuvant therapy (GEM-NAT) before surgery. GEM-NAT followed by surgical resection improve survival and R0 resection in BR-PDAC. Also, GEM-NAT may result in a good palliative option in non-resected patients because of progressive disease after neoadjuvant treatment. Results from randomized controlled trials (RCTs) are awaited to validate these findings.
| S-EPMC7431761 | biostudies-literature
Project description:PurposeClinical prognostic criteria using preoperative factors were not developed for post-neoadjuvant therapy (NAT) surgery of pancreatic ductal adenocarcinoma (PDAC). We aimed to identify preoperative factors associated with overall survival (OS) in PDAC patients who underwent post-NAT curative-intent surgery and develop risk stratification criteria.Materials and methodsConsecutive PDAC patients who underwent post-NAT curative-intent surgeries between 2007 and 2020 were retrospectively analyzed. Demographic, laboratory, surgical, and histopathologic variables were collected. Baseline, preoperative, and interval changes of computed tomography (CT) findings proposed by the Society of Abdominal Radiology and the American Pancreatic Association were analyzed. Cox proportional hazard analysis was used to select preoperative variables associated with OS. We developed risk stratification criteria composed of the significant preoperative variables, i.e., post-NAT response criteria. We compared the discrimination performance of post-NAT response criteria with that of post-NAT pathological (yp) American Joint Cancer Committee TNM staging system.ResultsOne hundred forty-five PDAC patients were included. Stable or increased tumor size on CT (hazard ratio [HR], 2.58; 95% confidence interval [CI], 1.58 to 4.21; p < 0.001) and elevated preoperative carbohydrate antigen 19-9 (CA19-9) level (HR, 1.98; 95% CI, 1.11 to 3.55; p=0.021) were independent factors of OS. The OS of the patient groups stratified by post-NAT response criteria which combined changes in tumor size and CA19-9 showed significant difference (p < 0.001). Such stratification was comparable to ypTNM staging in discrimination performance (difference of C-index, 0.068; 95% CI, -0.012 to 0.142).Conclusion"Any degree of decrease in tumor size on CT" and CA19-9 normalization or staying normal were independent favorable factors of OS. The combination of the two factors discriminated OS comparably to ypTNM staging.
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