Pre-Operative MDCT Staging Predicts Mesopancreatic Fat Infiltration—A Novel Marker for Neoadjuvant Treatment?

Summary: The rates of microscopic incomplete resections (R1/R0CRM+) in patients receiving standard pancreaticoduodenectomy for PDAC remain very high. One reason may be the reported high rates of mesopancreatic fat infiltration. In this large cohort study, we used available histopathological specimens of the retropancreatic fat and correlated high resolution CT-scans with the microscopic tumor infiltration of this area. We found that preoperative MDCT scans are suitable to detect cancerous infiltration of this mesopancreatic tissue and this, in turn, was a significant indicator for both incomplete surgical resection (R1/R0CRM+) and worse overall survival. These findings indicate that a neoadjuvant treatment in PDAC patients with CT-morphologically positive infiltration of the mesopancreas may result in better local control and thus improved resection rates. Mesopancreatic fat stranding should thus be considered in the decision for neoadjuvant therapy. Background: Due to the persistently high rates of R1 resections, neoadjuvant treatment and mesopancreatic excision (MPE) for ductal adenocarcinoma of the pancreatic head (hPDAC) have recently become a topic of interest. While radiographic cut-off for borderline resectability has been described, the necessary extent of surgery has not been established. It has not yet been elucidated whether pre-operative multi-detector computed tomography (MDCT) staging reliably predicts local mesopancreatic (MP) fat infiltration and tumor extension. Methods: Two hundred and forty two hPDAC patients that underwent MPE were analyzed. Radiographic re-evaluation was performed on (1) mesopancreatic fat stranding (MPS) and stranding to peripancreatic vessels, as well as (2) tumor diameter and anatomy, including contact to peripancreatic vessels (SMA, GDA, CHA, PV, SMV). Routinely resected mesopancreatic and perivascular (SMA and PV/SMV) tissue was histopathologically re-analyzed and histopathology correlated with radiographic findings. A logistic regression of survival was performed. Results: MDCT-predicted tumor diameter correlated with pathological T-stage, whereas presumed tumor contact and fat stranding to SMA and PV/SMV predicted and correlated with histological cancerous infiltration. Importantly, mesopancreatic fat stranding predicted MP cancerous infiltration. Positive MP infiltration was evident in over 78%. MPS and higher CT-predicted tumor diameter correlated with higher R1 resection rates. Patients with positive MP stranding had a significantly worse overall survival (p = 0.023). Conclusions: A detailed preoperative radiographic assessment can predict mesopancreatic infiltration and tumor morphology and should influence the decision for primary surgery, as well as the extent of surgery. To increase the rate of R0CRM− resections, MPS should be considered in the decision for neoadjuvant therapy.

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Impact of Neoadjuvant Therapy in Resected Pancreatic Ductal Adenocarcinoma of the Pancreatic Body or Tail on Surgical and Oncological Outcome: A Propensity-Score Matched Multicenter Study

Annals of Surgical Oncology ◽

10.1245/s10434-019-08137-6 ◽

2019 ◽

Vol 27 (6) ◽

pp. 1986-1996 ◽

Cited By ~ 2

Author(s):

Sanne Lof ◽

◽

Maarten Korrel ◽

Jony van Hilst ◽

Adnan Alseidi ◽

...

Keyword(s):

Overall Survival ◽

Pancreatic Fistula ◽

Pancreatic Ductal Adenocarcinoma ◽

Neoadjuvant Therapy ◽

Survival Benefit ◽

Pancreatic Head ◽

Ductal Adenocarcinoma ◽

Rank Test ◽

Pancreatic Body ◽

International Multicenter

Abstract Background Several studies have suggested a survival benefit of neoadjuvant therapy (NAT) for pancreatic ductal adenocarcinoma (PDAC) in the pancreatic head. Data concerning NAT for PDAC located in pancreatic body or tail are lacking. Methods Post hoc analysis of an international multicenter retrospective cohort of distal pancreatectomy for PDAC in 34 centers from 11 countries (2007–2015). Patients who underwent resection after NAT were matched (1:1 ratio), using propensity scores based on baseline characteristics, to patients who underwent upfront resection. Median overall survival was compared using the stratified log-rank test. Results Among 1236 patients, 136 (11.0%) received NAT, most frequently FOLFIRINOX (25.7%). In total, 94 patients receiving NAT were matched to 94 patients undergoing upfront resection. NAT was associated with less postoperative major morbidity (Clavien–Dindo ≥ 3a, 10.6% vs. 23.4%, P = 0.020) and pancreatic fistula grade B/C (9.6% vs. 21.3%, P = 0.026). NAT did not improve overall survival [27 (95% CI 14–39) versus 31 months (95% CI 19–42), P = 0.277], as compared with upfront resection. In a sensitivity analysis of 251 patients with radiographic tumor involvement of splenic vessels, NAT (n = 37, 14.7%) was associated with prolonged overall survival [36 (95% CI 18–53) versus 20 months (95% CI 15–24), P = 0.049], as compared with upfront resection. Conclusion In this international multicenter cohort study, NAT for resected PDAC in pancreatic body or tail was associated with less morbidity and pancreatic fistula but similar overall survival in comparison with upfront resection. Prospective studies should confirm a survival benefit of NAT in patients with PDAC and splenic vessel involvement.

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Neoadjuvant Treatment Lowers the Risk of Mesopancreatic Fat Infiltration and Local Recurrence in Patients with Pancreatic Cancer

Cancers ◽

10.3390/cancers14010068 ◽

2021 ◽

Vol 14 (1) ◽

pp. 68

Author(s):

Sami-Alexander Safi ◽

Lena Haeberle ◽

Alexander Rehders ◽

Stephen Fung ◽

Sascha Vaghiri ◽

...

Keyword(s):

Local Recurrence ◽

Neoadjuvant Therapy ◽

Treatment Response ◽

Tumor Response ◽

Neoadjuvant Treatment ◽

Ductal Adenocarcinoma ◽

R0 Resection ◽

Fat Infiltration ◽

Promising Tool ◽

Primary Surgery

Background: Survival following surgical treatment of ductal adenocarcinoma of the pancreas (PDAC) remains poor. The recent implementation of the circumferential resection margin (CRM) into standard histopathological evaluation lead to a significant reduction in R0 rates. Mesopancreatic fat infiltration is present in ~80% of PDAC patients at the time of primary surgery and recently, mesopancreatic excision (MPE) was correlated to complete resection. To attain an even higher rate of R0CRM− resections in the future, neoadjuvant therapy in patients with a progressive disease seems a promising tool. We analyzed radiographic and histopathological treatment response and mesopancreatic tumor infiltration in patients who received neoadjuvant therapy prior to MPE. The aim of our study was to evaluate the need for MPE following neoadjuvant therapy and if multi-detector computed tomographically (MDCT) evaluated treatment response correlates with mesopancreatic (MP) infiltration. Method: Radiographic, clinicopathological and survival parameters of 27 consecutive patients who underwent neoadjuvant therapy prior to MPE were evaluated. The mesopancreatic fat tissue was histopathologically analyzed and the 1 mm-rule (CRM) was applied. Results: In the study collective, both the rate of R0 resection R0(CRM−) and the rate of mesopancreatic fat infiltration was 62.9%. Patients with MP infiltration showed a lower tumor response. Surgical resection status was dependent on MP infiltration and tumor response status. Patients with MDCT-predicted tumor response were less prone to MP infiltration. When compared to patients after upfront surgery, MP infiltration and local recurrence rate was significantly lower after neoadjuvant treatment. Conclusion: MPE remains warranted after neoadjuvant therapy. Mesopancreatic fat invasion was still evident in the majority of our patients following neoadjuvant treatment. MDCT-predicted tumor response did not exclude mesopancreatic fat infiltration.

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Role of neoadjuvant treatment regimens for locally advanced pancreatic cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.3_suppl.444 ◽

2015 ◽

Vol 33 (3_suppl) ◽

pp. 444-444

Author(s):

Mohammad Alfayez ◽

Janet Shirley Graham ◽

Sally Hall ◽

David McIntosh ◽

Vivienne MacLaren ◽

...

Keyword(s):

Overall Survival ◽

Neoadjuvant Chemotherapy ◽

Neoadjuvant Therapy ◽

Locally Advanced ◽

Neoadjuvant Treatment ◽

Advanced Pancreatic Cancer ◽

Case Series ◽

Ductal Adenocarcinoma ◽

Anatomical Location ◽

Term Survival

444 Background: Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related mortality worldwide. Lymph node involvement and resection margin status play important roles in predicting relapse. Resectable disease occurs in only 15–20% of total patients who present with PDAC. Unfortunately, margin involvement (R1) occurs in 70–80% of these patients. Emerging evidence has shown that the use of neoadjuvant chemotherapy and localised radiotherapy to downsize the tumours and increase the margin clearance (R0) rate may improve the overall survival of PDAC patients.We report a neoadjuvant therapy approach in the non-clinical trial setting of our large, tertiary cancer centre. Methods: We prospectively collected the outcome data and toxicity of 53 patients diagnosed with borderline resectable or initially non-resectable PDAC between 2012 and 2014. These patients received either FOLFIRINOX (FFX) or Gemcitabine/Capecitabine (GemCap) combination chemotherapies. Following restaging by computed tomography (CT), the patients proceeded to preo-operative 5-FU-based chemo-radiotherapy, immediate resection or subsequent palliativetherapies. Results: The median age was 65 (range 30 – 79) at PDAC diagnosis. Sixty-one percent (n=32) were male with the commonest anatomical location being the head of the pancreas (58%, n=31). The median follow up for survivors is 13.7 months (range: 5.3–24.4). The median overall survival was 18.3 months (95%, CI: 12.0–24.5). There was no statistical difference between overall survival in patients receiving FFX and GemCap chemotherapies. The margin clearance rate (R0) was 36% (4/11) in patients who proceeded to resection after neoadjuvant chemotherapy alone. The rate was 100% (4/4) in patients who received additional chemoradiation prior to surgery. Conclusions: This case series reveals that neoadjuvant therapy improved survival of patients with PDAC. In addition, we showed an increase in the R0 resection rate in patients who underwent chemoradiation prior to surgery. Further work is ongoing but based on historical data we believe that this neoadjuvant approach may lead to a long term survival benefit.

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Factors affecting overall survival in ductal adenocarcinoma of the pancreatic head. Experience of one center

Malignant tumours ◽

10.18027/2224-5057-2021-11-1-20-28 ◽

2021 ◽

Vol 11 (1) ◽

pp. 20-28

Author(s):

D. M. Kuchin ◽

Ya. I. Kolesnik ◽

H. G. Torgomyan ◽

V. E. Zagainov

Keyword(s):

Overall Survival ◽

Adjuvant Chemotherapy ◽

Vascular Invasion ◽

Survival Rates ◽

Pancreatic Head ◽

Ductal Adenocarcinoma ◽

Factors Affecting ◽

Poorly Differentiated ◽

Well Differentiated ◽

Major Factors

Purpose. To identify major factors affecting the overall survival (OS). To select the cohort of patients with the best prognosis.Materials and methods. A retrospective analysis included data of 268 patients, 128 men and 140 women, with median age of 59±10,53 (30 to 83) years. For multivariate analysis of survival, patients were selected who underwent pancreaticoduodenectomy (PD) for ductal adenocarcinoma of the pancreatic head.Results. Our study demonstrated that histologically verified vascular invasion (detected only in 30 % of patients who underwent PD with resection of the major vessels) statistically significantly affected the OS. The increased CA19-9 level over 500 U / L (detected in 32,3 % of cases) is the factor that significantly worsens the OS. Patients with high grade adenocarcinoma have significantly better survival rates compared with patients who have moderately or poorly differentiated adenocarcinoma (p = 0.014; median 26 months, 95 % CI 4.4–47.6 versus median 17 months, 95 % CI 15–19, an median: 13 months, 95 % CI 5–21, respectively). Also, the use of adjuvant chemotherapy has a positive effect on long-term outcomes (p = 0.0001; median 26 months, 95 % CI 21.7–30.3 versus median 13 months, 95 % CI 11.3–14.7).Conclusion. A well-differentiated tumor and the use of adjuvant chemotherapy significantly increase the OS of patients. Poorly differentiated tumor, CA19-9 level over 500 U / mL and the histologically confirmed vascular invasion significantly worsen the prognosis of these patients.

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Adjuvant and Neoadjuvant Therapy for Pancreatic Adenocarcinoma

10.2310/7800.16076 ◽

2017 ◽

Author(s):

Gregory C Wilson ◽

Brent T Xia ◽

Syed A Ahmed

Keyword(s):

Pancreatic Cancer ◽

Adjuvant Therapy ◽

Neoadjuvant Therapy ◽

Pancreatic Adenocarcinoma ◽

Locally Advanced ◽

Neoadjuvant Treatment ◽

Advanced Pancreatic Cancer ◽

Treatment Strategies ◽

Ductal Adenocarcinoma ◽

Borderline Resectable

Despite decades of advancement and research into the multimodal care of pancreatic cancer, mortality after the diagnosis of pancreatic ductal adenocarcinoma remains grim. The role of adjuvant therapy following surgical resection has been well established in the literature. However, adjuvant therapy is imperfect, and outside of a clinical trial, there are high rates of omission or delayed initiation of therapy. Neoadjuvant treatment strategies continue to be explored in the management of resectable, borderline-resectable, and locally advanced unresectable pancreatic adenocarcinoma. With improved resection rates and the possibility for tumor downstaging, neoadjuvant therapy has become standard for patients with borderline-resectable and locally advanced unresectable tumors. Additional benefits of neoadjuvant therapy in the treatment of resectable tumors include improved completion rates of systemic therapy and R0 resection rates. Future clinical trials, including the use of novel treatment agents and combination treatment strategies in both neoadjuvant and adjuvant regimens, will add value to the treatment of pancreatic adenocarcinoma. Key words: adjuvant therapy, borderline-resectable pancreatic cancer, locally advanced pancreatic cancer, neoadjuvant therapy, pancreatic adenocarcinoma, resectable disease

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Neoadjuvant Therapy Followed by Resection Versus Upfront Resection for Resectable Pancreatic Cancer: A Propensity Score Matched Analysis

Journal of Clinical Oncology ◽

10.1200/jco.2016.68.5081 ◽

2017 ◽

Vol 35 (5) ◽

pp. 515-522 ◽

Cited By ~ 154

Author(s):

Ali A. Mokdad ◽

Rebecca M. Minter ◽

Hong Zhu ◽

Mathew M. Augustine ◽

Matthew R. Porembka ◽

...

Keyword(s):

Overall Survival ◽

Propensity Score ◽

Adjuvant Therapy ◽

Neoadjuvant Therapy ◽

Pancreatic Adenocarcinoma ◽

Early Stage ◽

Clinical Stage ◽

Pancreatic Head ◽

Hazard Ratio ◽

Stage I

Purpose To compare overall survival between patients who received neoadjuvant therapy (NAT) followed by resection and those who received upfront resection (UR)—as well as a subgroup of UR patients who also received adjuvant therapy—for early-stage resectable pancreatic adenocarcinoma. Patients and Methods Adult patients with resected, clinical stage I or II adenocarcinoma of the head of the pancreas were identified in the National Cancer Database from 2006 to 2012. Patients who underwent NAT followed by curative-intent resection were matched by propensity score with patients whose tumors were resected upfront. Overall survival was compared by using a Cox proportional hazards regression model. Early postoperative and oncologic outcomes were evaluated. Results We identified 15,237 patients with clinical stage I or II resected pancreatic head adenocarcinoma. From the NAT group, 2,005 patients (95%) were matched with 6,015 patients who underwent UR. The NAT group was associated with improved survival compared with UR (median survival, 26 months v 21 months, respectively; stratified log-rank P < .01; hazard ratio, 0.72; 95% CI, 0.68 to 0.78). Patients in the UR group had higher pathologic T stage (pT3 and T4: 86% v 73%; P < .01), higher positive lymph nodes (73% v 48%; P < .01), and higher positive resection margin (24% v 17%; P < .01). Compared with a subset of UR patients who received adjuvant therapy, NAT patients had a better survival (adjusted hazard ratio, 0.83; 95% CI, 0.73 to 0.89). Conclusion NAT followed by resection has a significant survival benefit compared with UR in early-stage, resected pancreatic head adenocarcinoma. These findings support the use of NAT, particularly as a patient selection tool, in the management of resectable pancreatic adenocarcinoma.

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External validation of three nomograms predicting survival using an international cohort of patients with resected pancreatic head ductal adenocarcinoma

British Journal of Surgery ◽

10.1093/bjs/znab202.032 ◽

2021 ◽

Vol 108 (Supplement_4) ◽

Author(s):

M Schneider ◽

I Labgaa ◽

D Vrochides ◽

A Zerbi ◽

G Nappo ◽

...

Keyword(s):

Lymph Nodes ◽

Sensitivity And Specificity ◽

Goodness Of Fit ◽

Neoadjuvant Treatment ◽

Pancreatic Head ◽

Tumor Grade ◽

Ductal Adenocarcinoma ◽

Youden Index ◽

Predictive Values ◽

Kaplan Meier

Abstract Objective Lymph node ratio (LNR, positive lymph nodes/collected lymph nodes during surgery) was identified as an important prognostic factor of survival in resected pancreatic cancer. Several nomograms based on LNR were recently proposed to predict survival after pancreatoduodenectomy (PD). The present study aimed to externally validate 3 published nomograms using an international cohort. Methods Consecutive patients with ductal adenocarcinoma of the pancreatic head who underwent PD without neoadjuvant treatment from 6 tertiary centers in Europe and the USA were retrospectively collected from 2000 to 2017. Patients with metastases at diagnosis, R2 resection, missing data regarding LNR, and who died within 90 postoperative days were excluded. The 3 selected nomograms were the updated Amsterdam nomogram (including LNR, adjuvant therapy, margin status, and tumor grade), the nomogram by Pu et al. (including LNR, age, tumor grade, and T stage) and the nomogram by Li et al. (including LNR, age, tumor location, grade, size, and TNM stage). Overall survivals (OS) were calculated using Kaplan-Meier method. For the validation, calibration (Hosmer-Lemeshow test), discrimination capacity (ROC curves for 3-year OS), and clinical utility (sensitivity and specificity at the value of Youden index) were assessed. Results After exclusion of 95 patients with metastases, R2 resection, and who died within 90 postoperative days, 1167 patients were included. Median OS of the entire cohort was 23 months (95% confidence interval: 21-24). For the 3 nomograms, Kaplan-Meier curves showed significant diminution of OS with increasing scores (p < 0.01 for the 3 nomograms). All nomograms showed good calibration (non significant Hosmer-Lemeshow goodness-of-fit tests). For the updated Amsterdam nomogram, the area under the ROC curve (AUROC) for 3-year OS was 0.66. Sensitivity and specificity were 73% and 50%. Regarding the nomogram by Pu et al., the AUROC was 0.67. Sensitivity and specificity were 65% and 60%. For the nomogram by Li et al., the AUROC was 0.67, while sensitivity and specificity were 56% and 71%. Conclusion The 3 selected nomograms were validated using an external international cohort and displayed interesting and comparable predictive values. Those nomograms may be used in clinical practice to estimate survival after PD for ductal adenocarcinoma.

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Neoadjuvant Treatment for Borderline Resectable Pancreatic Ductal Adenocarcinoma

Digestive Surgery ◽

10.1159/000493466 ◽

2018 ◽

Vol 36 (6) ◽

pp. 455-461 ◽

Cited By ~ 2

Author(s):

Benedikt Kaufmann ◽

Daniel Hartmann ◽

Jan G. D’Haese ◽

Pavel Stupakov ◽

Dejan Radenkovic ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Neoadjuvant Therapy ◽

Neoadjuvant Treatment ◽

Ductal Adenocarcinoma ◽

Preoperative Treatment ◽

Resectable Pancreatic Cancer ◽

Borderline Resectable ◽

Treatment Regimens ◽

Dismal Prognosis ◽

First Choice

One of the main reasons for the dismal prognosis of pancreatic ductal adenocarcinoma (PDAC) is its late diagnosis. At the time of presentation, only approximately 15–20% of all patients with PDAC are considered resectable and around 30% are considered borderline resectable. A surgical approach, which is the only curative option, is limited in borderline resectable patients by local involvement of surrounding structures. In borderline resectable pancreatic cancer (BRPC), neoadjuvant treatment regimens have been introduced with the rationale to downstage and downsize the tumor in order to enable resection and eliminate microscopic distant metastases. However, there are no official guidelines for the preoperative treatment of BRPC. In the majority of cases, patients are administered Gemcitabine-based or FOLFIRINOX-based chemotherapy regimens with or without radiation. Radiologic restaging after neoadjuvant therapy has to be judged with caution when it comes to predict tumor response and resectability, since inflammation induced by neoadjuvant therapy may mimic solid tumor. Patients who do not show any disease progression during neoadjuvant therapy should be offered surgical exploration, since a high percentage is likely to undergo resection with negative margins (R0) and, thus, achieve improved overall survival although imaging judged it unlikely. Despite the promising new approaches of neoadjuvant treatment regimens during the last 2 decades, surgery remains the first choice if the tumor appears to be primary resectable at the time of diagnosis. At present, there are no international guidelines regarding the preoperative treatment of BRPC. Therefore, in order to standardize and adjust neoadjuvant treatment in the future, new guidelines have to be determined on the basis of upcoming prospective randomized studies.

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Biomarker study in patients with resectable AJCC stage IIIc or stage IV (M1a) melanoma treated in a randomized phase II neoadjuvant trial.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.9047 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 9047-9047

Author(s):

Nitin Chakravarti ◽

Doina Ivan ◽

Merrick I. Ross ◽

Joseph L. Ilagan ◽

Carla L. Warneke ◽

...

Keyword(s):

Overall Survival ◽

Neoadjuvant Therapy ◽

Neoadjuvant Treatment ◽

Gene Array ◽

Stage Iiic ◽

Tumor Biopsy ◽

Term Survival ◽

Neoadjuvant Systemic Therapy ◽

Biomarker Analysis ◽

Definitive Surgery

9047 Background: Fewer than 30% of patients with resectable stage IIIC or IV (M1a) metastatic melanoma (MetM) who undergo surgical resection will achieve long-term survival. This study was designed to administer neoadjuvant systemic therapy prior to definitive surgery to explore potential predictive and prognostic biomarkers in patients with MetM. Methods: Fifty patients with resectable MetM were randomized to receive temozolomide (TMZ) alone at 150 mg/m2/day x 7 days every other week (Arm A, n=26) or with pegylated interferon (PGI) at 0.5 mcg/kg weekly (Arm B, n=24). After a pre-treatment tumor biopsy, patients received 8 weeks of neoadjuvant therapy before undergoing surgery. Endpoints were clinical response, tolerability, and biomarker analysis by immunohistochemistry and gene array. In particular, we examined PD-1, PD-L1, pAKT, pMAPK, Ki67, and caspase 3. Patients with response (complete-, partial-, or stable disease) received up to 3 additional cycles of the assigned regimen as adjuvant therapy. Results: Overall response to neoadjuvant therapy was 38% [1 CR, 15 PRs, 3 SDs]: 31% in Arm A (95% CI 14% - 52%) and 46% in Arm B (95% CI 26% - 67%). Estimated 4-year overall survival was 52.52% (95% CI 35.86 - 66.74%). Only 5 patients did not undergo definitive surgery after neoadjuvant treatment due to development of distant metastasis. Preliminary data indicate that in Arm B, responders had higher PD-1 membranous expression in tumor infiltrating lymphocytes (TILs) (p=0.029). Furthermore, low PD-L1 cytoplasmic expression in TILs (p=0.002) as well as low nuclear PD-L1 expression in tumor cells (p=0.025) had better overall survival. Conclusions: Comparing with historical data, neoadjuvant therapy has a potential to improve overall survival in patients with resectable MetM. Biomarker analysis may predict response to neoadjuvant treatment as well as overall survival. Clinical trial information: NCT00525031.

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Impact of G-CSF during neoadjuvant therapy on outcomes of operable pancreatic cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.4126 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 4126-4126

Author(s):

Pranav Murthy ◽

Mazen S Zenati ◽

Samer S. AlMasri ◽

Aatur D. Singhi ◽

Annissa DeSilva ◽

...

Keyword(s):

Pancreatic Cancer ◽

Overall Survival ◽

Neoadjuvant Therapy ◽

Tumor Staging ◽

Neutrophil Extracellular Trap ◽

Oncologic Outcomes ◽

Ductal Adenocarcinoma ◽

Common Side Effect ◽

Interleukin 17 ◽

The Impact

4126 Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease characterized by chronic inflammation and a tolerogenic immune response. Neutropenia is a common side effect of cytotoxic chemotherapy, managed with administration of recombinant granulocyte-colony stimulating factor (G-CSF, Filgrastim). The interleukin 17 – G-CSF – neutrophil extracellular trap (NET) axis promotes oncogenesis and progression of PDAC, inhibiting adaptive immunity. We evaluated the impact of G-CSF administration during neoadjuvant therapy (NAT) on oncologic outcomes in patients with operable pancreatic cancer. Methods: A retrospective review of all patients with localized PDAC treated with NAT prior to pancreatic resection between 2014 – 2020 was completed at a single institution. G-CSF administration, type, and dose were collected from inpatient and outpatient medical records. Results: Of 351 patients treated, 138 (39%) received G-CSF during NAT with a median follow-up of 45.8 months. Patients who received G-CSF were younger (64.0 vs 66.7, p = 0.008), had lower BMI (26.5 vs 27.9, p = 0.021), and were more likely to receive 5-FU based chemotherapy (42% vs 28.2%, p < 0.0001), NAT dose reduction (40.6% vs 25.4%, p = 0.003), or experience febrile neutropenia (8.7% vs 3.3%, p = 0.029). No differences were observed in baseline or pathologic tumor staging. In patients who received G-CSF, 130 (94%) received Pegfilgrastim with a median cumulative dose of 12 mg (IQR 6-12). Patients who received G-CSF were more likely to have an elevated post-NAT neutrophil to lymphocyte ratio (45% vs 29.6%, p = 0.004) and systemic immune-inflammation index (39.5% vs 29.6%, p = 0.061). Receiving G-CSF was an independent predictor of perineural invasion (HR 2.4, 95 CI [1.08, 5.5], p = 0.031) and margin positive resection (HR 1.69, 95 CI [1.01, 2.83], p = 0.043). Patients who received G-CSF had decreased overall survival compared to patients who did not receive G-CSF (median OS: 29.2 vs 38.7 months, p = 0.0001). Receiving G-CSF during NAT was an independent negative predictor of progression free (HR 1.38, 95 CI [1.04, 1.83], p = 0.022) and overall survival (HR 2.02, 95 CI [1.45, 2.79], p < 0.0001). In a subset of patients with available pre- and post-NAT serum specimens (n = 28), G-CSF administration resulted in an increased number of citrullinated histone H3 complexes following NAT (+1378±1502 vs -300.7±1147 pg/ml, p = 0.007), indicative of enhanced peripheral NET formation. Conclusions: In patients with localized PDAC receiving NAT prior to surgical extirpation, G-CSF administration is associated with worse oncologic outcomes and should be administered with caution. Prospective randomized as well as confirmatory clinical studies are in order.

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