Identification of MicroRNA-21 as a Biomarker for Chemoresistance and Clinical Outcome Following Adjuvant Therapy in Resectable Pancreatic Cancer

448 Background: Meta-analysis of smaller studies have shown that neoadjuvant chemotherapy is more beneficial for patients with resectable pancreatic cancer than upfront surgery by comparing life expectancy (LE) and quality-adjusted life expectancy (QALE) computed from Markov models. The study results utilized literature data using several small clinical trials but no individual patient data was used and only gemzar based therapy was studied. Methods: Markov model was used to calculate the LE and QALE for adjuvant and neoadjuvant chemotherapy and individual patient parameters was used in the model to refine certain clinical outcome datapoints. We used 278 patients pancreatic cancer data from 2008 to 2017 from Stony Brook University and used the literature data from randomized clinical trials studying gemzar (GEM), gemzar and capecitabine (GEM+CAP) and modified FOLFIRINOX (mFOL). The median OS for each model was obtained by computer simulation. Results: Intensive adjuvant chemotherapy using mFOL had best simulation outcome with median OS (52.5 months), LE (81.5 months), and QALE (65.0 quality-adjusted life months) compared to using GEM (40.5, 66.5, and 52.9 months for median OS, LE, and QALE), GEM+CAP (16.5, 28.0, and 21.9 months for median OS, LE, and QALE), and 5-FU (16.5, 26.9, and 21.1 months for median OS, LE, and QALE). The neoadjuvant chemotherapy approach improved LE and QALE but not in median OS when compared to adjuvant therapy. Conclusions: Mathematical modeling confirms the improved clinical outcome for modified FOLFIRINOX in resectable pancreatic cancer. The benefit of neoadjuvant chemotherapy approach suggest further clinical trials are needed to determine the better treatment strategy for pancreatic cancer patients.

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Neoadjuvant therapy versus upfront surgery in resectable pancreatic cancer according to intention-to-treat and per-protocol analysis: A systematic review and meta-analysis

Scientific Reports ◽

10.1038/s41598-019-52167-9 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 6

Author(s):

Yoon Suk Lee ◽

Jong-Chan Lee ◽

Se Yeol Yang ◽

Jaihwan Kim ◽

Jin-Hyeok Hwang

Keyword(s):

Pancreatic Cancer ◽

Adjuvant Therapy ◽

Neoadjuvant Therapy ◽

Protocol Analysis ◽

Meta Analysis ◽

Statistical Significance ◽

Supporting Evidence ◽

Resectable Pancreatic Cancer ◽

Survival Gain ◽

Intention To Treat

Abstract The effectiveness of neoadjuvant therapy (NAT) remains unclear in resectable pancreatic cancer (PC) as compared with upfront surgery (US). The aim of this study was to investigate the survival gain of NAT over US in resectable PC. PubMed and EMBASE were searched for studies comparing survival outcomes between NAT and US for resectable PC until June 2018. Overall survival (OS) was analyzed according to treatment strategy (NAT versus US) and analytic methods (intention-to-treat analysis (ITT) and per-protocol analysis (PP)). In 14 studies, 2,699 and 6,992 patients were treated with NAT and US, respectively. Although PP analysis showed the survival gain of NAT (HR 0.72, 95% CI 0.68–0.76), ITT analysis did not show the statistical significance (HR 0.96, 95% CI 0.82–1.12). However, NAT completed with subsequent surgery showed better survival over US completed with adjuvant therapy (HR 0.82, 95% CI 0.71–0.93). In conclusion, the supporting evidence for NAT in resectable PC was insufficient because the benefit was not demonstrated in ITT analysis. However, among the patients who completed both surgery and chemotherapy, NAT showed survival benefit over adjuvant therapy. Therefore, NAT could have a role of triaging the patients for surgery even in resectable PC.

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Are We Sure that Adjuvant Chemotherapy is the Best Approach for Resectable Pancreatic Cancer? Are We in the Era of Neoadjuvant Treatment? A Review of Current Literature

Journal of Clinical Medicine ◽

10.3390/jcm8111922 ◽

2019 ◽

Vol 8 (11) ◽

pp. 1922 ◽

Cited By ~ 3

Author(s):

Oneda ◽

Zaniboni

Keyword(s):

Pancreatic Cancer ◽

Adjuvant Chemotherapy ◽

Adjuvant Therapy ◽

Performance Status ◽

Neoadjuvant Treatment ◽

Early Recurrence ◽

Current Treatment ◽

R0 Resection ◽

Resectable Pancreatic Cancer ◽

Advantages And Disadvantages

The outcome of pancreatic cancer is poor, with a 9% 5-year survival rate. Current treatment recommendations in the 10%–20% of patients who present with resectable disease support upfront resection followed by adjuvant therapy. Until now, only early complete surgical (R0) resection and adjuvant chemotherapy (AC) with either FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) or nab-paclitaxel plus gemcitabine have been shown to prolong the survival. However, up to 30% of patients do not receive adjuvant therapy because of the development of early recurrence, postoperative complications, comorbidities, and reduced performance status. The aims of neoadjuvant chemotherapy (NAC) are to identify rapidly progressing patients to avoid futile surgery, eliminate micrometastases, increase the feasibility of R0 resection, and ensure the completion of multimodal treatment. Neoadjuvant treatments are effective, but there is no consensus on their use in resectable pancreatic cancer (RPC) because of its lack of a survival benefit over adjuvant therapy. In this review, we analyze the advantages and disadvantages of the two therapeutic approaches in RPC. We need studies that compare the two approaches and can identify the appropriate sequence of adjuvant therapy after neoadjuvant treatment and surgery.

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Neoadjuvant vs Adjuvant Therapy for Resectable Pancreatic Cancer: The Evolving Role of Radiation

Seminars in Radiation Oncology ◽

10.1016/j.semradonc.2013.11.002 ◽

2014 ◽

Vol 24 (2) ◽

pp. 113-125 ◽

Cited By ~ 9

Author(s):

Sarah Hoffe ◽

Nikhil Rao ◽

Ravi Shridhar

Keyword(s):

Pancreatic Cancer ◽

Adjuvant Therapy ◽

Resectable Pancreatic Cancer

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Engraftment of resected pancreatic adenocarcinoma in SCID mice and patient survival following surgical resection: Roswell Park's experience.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.3_suppl.185 ◽

2014 ◽

Vol 32 (3_suppl) ◽

pp. 185-185

Author(s):

Jose Luis Aranez ◽

Potjana Jitawatanarat ◽

Bonnie Hylander ◽

Rose Pitoniak ◽

Charles Levea ◽

...

Keyword(s):

Pancreatic Cancer ◽

Clinical Outcome ◽

Pancreatic Adenocarcinoma ◽

Prognostic Marker ◽

Statistical Significance ◽

Scid Mice ◽

Resectable Pancreatic Cancer ◽

Baseline Information ◽

Potential Link ◽

Index Value

185 Background: Preclinical models developed by implanting resected pancreatic cancer from human donors into immunocompromised (SCID) mice have been valuable in understanding the disease’s biology and developing therapies. The ability of resected tumors to engraft successfully has previously been reported to be a poor prognostic marker. This study was conducted to investigate the relationship between successful engraftment and clinical outcome by analyzing such a model developed at Roswell Park over the last decade. Methods: A retrospective review of 48 donor patients (27 males and 21 females) whose resected pancreatic adenocarcinoma was xenografted in SCID mice between 1999-2009 was conducted. The clinical outcome and baseline information were correlated with engraftment outcome. The expression of potential biomarkers correlating with engraftment was evaluated by performing immunohistochemistry on the initial donor surgical specimens. The expression was scored, assigned an average index value and categorized into groups (High vs Low expression) based on a median cutoff of values. Results: Resected tumors from 21 of the 48 donors successfully engrafted when implanted subcutaneously in SCID mice (44%). The baseline demographics and disease characteristics were balanced between engrafters versus non-engrafters. All of the engrafters and 26 (of 27) of non-engrafters received adjuvant treatment. The 2-year overall survival (OS) of patients whose tumors successfully engrafted was 17% compared to 39% in those whose tumors failed to engraft (P=0.09; hazard ratio 1.305 [95% CI 0.717-2.375]). Analysis to identify potential biological markers associated with engraftment success is underway. Conclusions: A review of the clinical outcome of patients whose tumors were procured and used for the patient-derived primary pancreatic cancer xenograft program at Roswell Park showed that successful engraftment in SCID mice is potentially a poor prognostic marker in patients with resectable pancreatic cancer. Our analysis did not reach statistical significance which is likely due to a smaller sample size but the potential link is consistent with that reported by others.

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Propensity score matched analysis of neoadjuvant therapy for resectable pancreatic cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.4_suppl.381 ◽

2017 ◽

Vol 35 (4_suppl) ◽

pp. 381-381

Author(s):

Kenneth L Meredith ◽

Jamie Huston ◽

Anjan Jayantilal Patel ◽

Richard H. Brown ◽

Fadi Kayali ◽

...

Keyword(s):

Pancreatic Cancer ◽

Propensity Score ◽

Adjuvant Therapy ◽

Neoadjuvant Therapy ◽

Cancer Patients ◽

Tumor Size ◽

Survival Benefit ◽

Categorical Variables ◽

Resectable Pancreatic Cancer ◽

The Impact

381 Background: Neoadjuvant therapy (NT) for resectable pancreatic cancer continues to be debated. There is little data to demonstrate survival benefit over patients who were treated with up front surgery (UFS) vs NT. We sought to examine the impact of neoadjuvant chemotherapy (NCT), neoadjuvant chemoradiation (NCRT), and UFS on survival in pancreatic cancer patients. Methods: The NCDB was accessed to identify patients with pancreatic adenocarcinoma. Propensity score matching (PSM) was performed against age, tumor size, margin status, and institutional surgery volume. Patient characteristics (continuous and categorical variables) were compared using Mann-Whitney U, Kruskal Wallis and Pearson’s Chi-square test as appropriate. Survival analyses were performed using the Kaplan-Meier method. Multivariable cox proportional hazard models (MVA) were developed to identify predictors of survival. All statistical tests were two-sided and α < 0.05 was considered significant. Results: After PSM, 5,034 patients (UFS 2,517; NT 2,517: 1,143 NCT and 1,374 NCRT) were included in the analysis. There was no difference in age, tumor size, or grade among cohorts. The mean nodes positive were 1.6 ± 2.6 in NT and 2 ± 3.3 in UFS, p = 0.02. In the pre-matched cohort R0 resections were performed in 75.9% UFS, 82.9% NCRT, and 79.6% NCT, p < 0.001. The median and 5 year survival for NCT, NCRT and UFS was 28.6 months and 25.2%, 25.7 months and 22.2%, and 21.3 months and 21.7%, p < 0.001. Adjuvant therapy (chemotherapy (CT) or CRT) in the UFS did demonstrate a survival benefit 22.5 months vs 18.6 months, p < 0.001, however this did not benefit NCT or NCRT, p = 0.8 and p = 0.8 respectively. Additionally survival in the UFS with adjuvant therapy either CT or CRT was still decreased compared to either NCT or NCRT, p < 0.001 and p = 0.001 respectively. MVA demonstrated that age, T-stage, lymph nodes positive, R0 resection, grade, NCT and NCRT were predictors of survival. Conclusions: Neoadjuvant therapy improves survival in resectable pancreatic cancer patients. NCT and NCRT demonstrated survival benefit compared to UFS even with adjuvant therapy. Patients with resectable pancreatic cancer should be considered for neoadjuvant therapy.

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