Unresectable Pancreatic Cancer Patients Research Articles

Abstract LB_C05: A novel approach to convert non-resectable pancreatic cancer with major artery involvement using endovascular activation of Padeliporfin by vascular-targeted photodynamic therapy

Abstract Pancreatic cancer is a fatal disease: the patient usually has a very poor prognosis and limited treatment options. It is projected to be the second leading cause of cancer-related death by 2030. It is estimated that 80% of patients have metastatic or localized disease with vascular involvement at presentation, not amenable to surgery. Thus, a therapy that will convert unresectable, due to vascular involvement, tumors to resectable is an unmet medical need. We developed a novel treatment relying on endovascular activation of a photosensitizer Padeliporfin, by a vascular-targeted photodynamic therapy (VTP) to clear the artery from the encasing tumor enabling surgery. Padeliporfin is administered intravenously and activated locally by illumination via an optical fiber, deployed within the tumor encased artery by an angioplasty procedure under fluoroscopy. In a proof-of-concept study in normal swine model, treatment induced areas of ablation in normal pancreatic parenchyma while sparing the artery and other major structures in it’s vicinity. Drug and light doses used were proved effective in other solid tumors in preclinical and clinical studies. Safety was evaluated in a controlled study comprised of 12 pigs subjected to Padeliporfin VTP in a superior mesenteric artery (SMA). Two light doses were tested. Control groups received no drug or no illumination and drug. Follow up was 48 hours or seven days post treatment. Clinical observations and blood test results did not reveal any signs of decreased wellness without differences between treated and control groups. Lipase results were unchanged compared to the baseline. Amylase levels were within the normal range in all animals. Histopathology findings 48 hours post VTP in the SMA and surrounding tissues were similar in treated and control animals. Observed changes were manifested as small lesions consistent with angioplasty procedure impact, involving less than 25% of the media circumference. Small foci of coagulative necrosis were observed in the pancreatic parenchyma in the vicinity of SMA. In the seven-day samples, there was media pressure necrosis in occasional sections of the artery in all groups involving less than 25% of the circumference, attributed to the angioplasty procedure. Minimal fibrosis in a few samples, consisted of focal areas of fibroblast proliferation, indicating early regeneration, with no architectural or thickness changes of the arterial wall. The tissues surrounding SMA as well as organs downstream to the treated artery were mostly within normal ranges. Our results demonstrate that endovascular Padeliporfin VTP is feasible and has an acceptable safety profile together with evidence of ability to ablate pancreatic tumors encasing major abdominal arteries. The efficacy is further supported by our studies showing effective tumor ablations in orthotopic mouse models especially in combination with immune modulating therapies. A phase I trial (NCT5918783) aims to evaluate the potential of this approach for converting unresectable pancreatic cancer patients to amenable for surgery. Citation Format: Dina Preise, Yaniv Cohen, Genia Alpert, Zachary Sacks, Tamar Yechezkel, Natalia Kudinova, Eyal Morag, Ehud Willenz, Julia Rothman, Keren Brook, Inna Krasnopolskaya, Lilach Agemy, Sofia Zilber, Hooman Yarmohammadi, David Kelsen, David Perry, Avigdor Scherz. A novel approach to convert non-resectable pancreatic cancer with major artery involvement using endovascular activation of Padeliporfin by vascular-targeted photodynamic therapy [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_C05.

152P Interim analysis of the NAPOLEON-2 study: Safety evaluation of nanoliposomal irinotecan with fluorouracil and folinic acid for unresectable pancreatic cancer patients with prior biliary drainage

152P Interim analysis of the NAPOLEON-2 study: Safety evaluation of nanoliposomal irinotecan with fluorouracil and folinic acid for unresectable pancreatic cancer patients with prior biliary drainage

Induction Chemotherapy Followed by Concomitant Chemoradiation using Intensity Modulated Radiotherapy Technique in Locally Advanced Unresectable Pancreatic Cancer patients

Induction Chemotherapy Followed by Concomitant Chemoradiation using Intensity Modulated Radiotherapy Technique in Locally Advanced Unresectable Pancreatic Cancer patients

C-reactive protein/albumin ratio is the most significant inflammatory marker in unresectable pancreatic cancer treated with FOLFIRINOX or gemcitabine plus nab-paclitaxel

There are limited absolute biomarkers for determining the prognosis before first- and second-line palliative chemotherapy in unresectable pancreatic cancer (urPC) patients. To find the best prognostic inflammatory marker, we investigated relationships between overall survival (OS) and six inflammatory markers; C-reactive protein/albumin ratio (CAR), neutrophil–lymphocyte ratio (NLR), prognostic nutrition index (PNI), platelet–lymphocyte ratio (PLR), Glasgow prognostic score (GPS), and prognostic index (PI). We examined 255 patients who received gemcitabine + nab-paclitaxel or FOLFIRINOX as first-line chemotherapy and 159 patients who subsequently underwent second-line chemotherapy. First-line patients with lower CAR had better OS compared to those with a higher CAR (hazard ratio 0.57; 95% confidential index 0.42–77; P < 0.01). Similarly, lower NLR (P = 0.01), higher PNI (P = 0.04), lower PLR (P = 0.03), GPS score of 0 (P < 0.01) and PI score of 0 (P < 0.01) were all associated with better OS. CAR demonstrated the best superiority for determining survival prognosis through the use of area under the curve of time-dependent receiver-operating characteristic curves. Furthermore, a lower CAR before second-line therapy exhibited better OS versus higher CAR (P < 0.01). Therefore, CAR might be a useful biomarker for predicting urPC patient prognosis in both first- and second-line chemotherapy.

Electronic patient-reported outcome measured in patients with pancreatic cancer receiving second-line chemotherapy: A multicenter prospective observational study.

682 Background: Pancreatic cancer and especially late-line chemotherapy often negatively impact patient quality of life (QoL). However, QoL outside of the date of hospital visits has not been adequately evaluated. This study assessed QoL at home in patients receiving chemotherapy using electronic patient-reported outcomes (ePRO). Methods: This multicenter prospective observational study was conducted in 29 Japanese centers. Pathologically confirmed unresectable pancreatic cancer patients who were going to receive a second cycle of second-line chemotherapy, liposomal irinotecan plus fluorouracil/leucovorin (nal-IRI+FF), gemcitabine plus nab-paclitaxel (GEM+nab-PTX), or gemcitabine alone (GEM) at the outpatient department were included. QoL was assessed by electronic instruments on days 1, 2, 4, 6, 8, and 11 of each administration during two consecutive cycles (second and third cycles). The primary outcome was the index value of EuroQol 5-dimensions 5-levels (EQ-5D-5L). Secondary outcomes were the status of the European Organization for Research and Treatment of Cancer (EORTC)-QLQ-C30 and Patient-Reported Outcome Common Terminology Criteria for Adverse Events (PRO-CTCAE). Results: A total of 90 patients, 56 receiving nal-IRI+FF, 27 receiving GEM+nab-PTX, and 7 receiving GEM, were eligible for this study. The patients who responded to at least the first questionnaire and received nal-IRI+FF (n = 46) or GEM+nab-PTX (n = 16) were selected for analysis. In the nal-IRI+FF group, the mean index value of EQ-5D-5L on day 1 of the second cycle was 0.803±0.142, declined up to day 6 (0.678±0.247), and had recovered by day 1 of the third cycle (0.776±0.197). Similar trends were observed in the third cycle; the nadir of the mean index value was 0.723±0.182 on day eight and had recovered by day 15 (0.782±0.159). On the other hand, in the GEM+nab-PTX group, the nadir of the mean index value in the second cycle was on day 6 of the third administration (0.751±0.184) and had not fully recovered by day 1 of the third cycle (0.789±0.182). For global health status according to EORTC-QLQ-C30, a similar trend to EQ-5D-5L was observed in both groups. According to the results of the PRO-CTCAE, pain (40.4%), diarrhea (36.5%), abdominal pain (30.8%), fatigue (28.8%), and anorexia (28.8%) were frequent severe or very severe adverse events in the nal-IRI+FF group. In comparison, diarrhea (29.2%) and anorexia (25.0%) were frequent severe or very severe adverse events in the GEM+nab-PTX group. Conclusions: QoL assessed by ePRO outside the date of hospital visits revealed the pattern or details of QoL transition. Further study is needed so that these trends can be taken into account in the management of chemotherapy. Clinical trial information: UMIN000044245 .

Normalization of tumor markers and a clear resection margin affect progression-free survival of patients with unresectable pancreatic cancer who have undergone conversion surgery

BackgroundWith the advent of intensive combination regimens, an increasing number of patients with unresectable pancreatic cancer (UPC) have regained the opportunity for surgery. We investigated the clinical benefits and prognostic factors of conversion surgery (CS) in UPC patients.MethodsWe retrospectively enrolled patients with UPC who had received CS following first-line systemic treatment in our center between 2014 to 2022. Treatment response, safety of the surgical procedure and clinicopathological data were collected. We analyzed the prognostic factors for postoperative survival among UPC patients who had CS.ResultsSixty-seven patients with UPC were enrolled (53 with locally advanced pancreatic cancer (LAPC) and 14 with metastatic pancreatic cancer (MPC)). The duration of preoperative systemic treatment was 4.17 months for LAPC patients and 6.52 months for MPC patients. All patients experienced a partial response (PR) or had stable disease (SD) preoperatively according to imaging. Tumor resection was unsuccessful in four patients and, finally, R0 resection was obtained in 81% of cases. Downstaging was determined pathologically in 87% of cases; four patients achieved a complete pathological response. Median postoperative-progression-free survival (PO-PFS) was 9.77 months and postoperative overall survival (PO-OS) was 31.2 months. Multivariate logistic regression analyses revealed that the resection margin and postoperative changes in levels of tumor markers were significant prognostic factors for PO-PFS. No factors were associated significantly with PO-OS according to multivariate analyses.ConclusionsCS is a promising strategy for improving the prognosis of UPC patients. The resection margin and postoperative change in levels of tumor markers are the most important prognostic factors for prolonged PFS. Multidisciplinary treatment in high-volume centers is strongly recommended. Prospective studies must be undertaken to resolve the various problems regarding optimal regimens, the duration of treatment, and detailed criteria for CS.

Impact of the COVID-19 Pandemic on the Management and End-of-life Care of Unresectable Pancreatic Cancer.

Objective The coronavirus disease (COVID-19) pandemic has altered the delivery of medical care. The present study evaluated the impact of COVID-19 on the outcomes of unresectable pancreatic cancer (PC) patients who received end-of-life care. Methods We retrospectively compared the management of PC patients during the COVID-19 pandemic (from April 2020 to March 2021) to the preceding year, which was unaffected by the pandemic (from April 2019 to March 2020), based on a prospectively maintained institutional database. Results A total of 178 patients were included in the COVID-19-exposed group and 201 patients were included in the COVID-19-unexposed group. The median overall survival was similar between the groups (exposed vs. unexposed: 12.6 vs. 11.9 months, p = 0.174). Treatment regimens and relative dose intensities and the progression-free survival of GnP (gemcitabine in combination with nab-paclitaxel) and mFOLFIRINOX as first- and second-line chemotherapy did not differ significantly between the two groups. Only 9.0% of patients died at home in the COVID-19-unexposed group, compared to 32.0% in the COVID-19-exposed group (p <0.001). A multivariate analysis revealed that death during the COVID-19 exposed period was independently associated with home death (odds ratio: 4.536, 95% confidence interval: 2.527-8.140, p <0.001). Conclusions While the COVID-19 pandemic did not seem to influence chemotherapeutic treatment for PC patients at our institution, it had a large impact on end-of-life care. These findings may promote discussion about end-of-life care in Japan.

Genetic medicine in companion diagnostics of germline BRCA testing of Japanese pancreatic cancer patients.

In 2021, Japan's national health insurance made germline BRCA (g.BRCA) testing available to unresectable pancreatic cancer (PC) patients as a companion diagnostic (CD) of the PARP inhibitor. This study investigated the incidence of the g.BRCA variant (g.BRCAv.) and the status of the genetic medicine associated with its testing. A total of 110 PC patients underwent the testing, five of whom (4.5%) had a deleterious g.BRCA2v. (all truncations) but no g.BRCA1v. The turnaround time (TAT) to the doctors was 13 days, and to the patients, 17 days. A higher incidence of a BRCA-related family history and a shorter TAT were seen in the g.BRCAv. patients, but they were insignificant (p = 0.085 and p = 0.059, respectively). Genetic counseling was not performed for three g.BRCA2v. patients because two of them had no accessible relatives and one died of the cancer before the genetic report was completed. Two families underwent generic counseling and testing based on the patient's genetic data. g.BRCAv. is recognized in a small fraction of PC cases, and the following genetic counseling is done more for the relatives than for the patients. TAT was constant and did not affect much on the genetic counseling, but the earlier testing is expected for patients with a deadly cancer.

Real-world evaluation of AG plus PD-1 antibody in old patients with advanced unresectable pancreatic cancer.

e16226 Background: Unresectable pancreatic cancer (PC) is associated with fatal outcomes despite chemotherapy and radiation. PD-1 antibodies might provide favorable long-term survival in combination with chemotherapy according to previous clinical trials and pilot studies. In this study, we conducted a real-world evaluation of PD-1 antibody in old patients with unresectable PC. We also aimed to explore biomarkers for the early prediction of PD-1 antibodies response. Methods: This is a single-arm, single-center, real-world study. Primary Objectives: ORR. Secondary Objectives: DCR, OS, PFS, Safety(CTCAE). Exploratory Objectives: The alteration of molecular biomarkers to PD-1 antibodies treatment including IL-2, IL-4, IL-10, IL-16, TNF¦Á and IFN-¦Ã, ect. Key eligibility criteria: Histopathologically confirmed advanced unresectable PC; Without systematic treatment; ¡Ý60 years old; ECOG PS 0 or 1; Evaluated by mRECIST PD-1 plus AG, Q3W Surgery Until disease progression, unacceptable toxicity, or up to 2 years. Results: From Jan 2021 to Dec 2021, 10 unresectable PC patients were enrolled in Yuhang campus, the first affiliated hospital, Zhejiang university school of medicine, which their baseline characteristics were listed in Table. A total of 9 patients were finally included and analyzed. Clinical decisions were made by multi-disciplinary team. The treatment efficacy was evaluated by mRECIST. A total of 9 patients were assessable for response. ORR was 33.3%, with 3/9 partial response (PR). 5/9 patients were stable disease (SD), and DCR was 88.9%. Conversion therapy uses rational immunotherapy and chemotherapy and so on combined with MDT assessment to translate initial unresectable case to resectable one, which obviously prolongs survival time and improves quality of life. For patients with surgically unresectable PC 2 patients were successfully transformed. The rate of overall surgical conversions was 22.2%. The most common adverse events were anemia (6 [60%] patients). There were no treatment-related level 4 and 5 adverse events. There was no treatment-related cardiotoxicity. No patients were interrupted due to adverse events. Conclusions: PD-1 antibody plus Chemotherapy demonstrates significant clinical activity and favorable tolerability in old patients with advanced unresectable PC, and DCR was 88.9%.[Table: see text]

A phase II study of nivolumab in combination with modified FOLFIRINOX for metastatic pancreatic cancer.

553 Background: Although FOLFIRINOX and nab-paclitaxel plus gemcitabine have improved the survival of unresectable pancreatic cancer patients, high unmet medical needs still exist for the treatment of this cancer. Nivolumab has shown efficacy for multiple cancer types in not only its monotherapy but also combinations with conventional chemotherapies. This study aimed to assess the efficacy and safety of nivolumab in combination with modified FOLFIRINOX, which is one of the first line chemotherapy for pancreatic cancer. Methods: Thirty-one treatment-naïve patients with metastatic, unresectable/recurrent pancreatic cancer patients received nivolumab (480 mg, every 4 weeks) plus modified FOLFIRINOX (oxaliplatin 85 mg/m2, levofolinate 200 mg/m2, irinotecan 150 mg/m2 and fluorouracil 2400 mg/m2, every 2 weeks). The primary endpoint was objective response rate (ORR) (central assessment). Secondary endpoints were overall survival (OS), progression-free survival (PFS) (central assessment), safety etc. Results: The median duration of follow-up was 13.40 months. ORR was 32.3% (CR: 0.0%, PR: 32.3%) and the median duration of response was 7.36 (range 3.5-20.1+) months. Median OS and PFS were 13.40 (90% CI 10.87-15.24) months and 7.39 (90% CI 3.88-7.59) months, respectively. The 1-year survival rate was 54.8 (90% CI 39.1-68.1) %. The most frequently reported grade 3-4 drug-related adverse events were neutrophil count decreased (38.7%), decreased appetite (16.1%), hypokalemia (12.9%), febrile neutropenia (9.7%), nausea (9.7%) and white blood cell count decreased (9.7%). Adrenal insufficiency (3.2%) was observed as immune mediated adverse event. Conclusions: Nivolumab in combination with modified FOLFIRINOX had a manageable safety profile in patients with metastatic pancreatic cancer. Additional work is needed to determine the population who can benefit from the combination. Clinical trial information: JapicCTI-184230.

Competing Risk Analysis of Outcomes of Unresectable Pancreatic Cancer Patients Undergoing Definitive Radiotherapy.

PurposeWe investigated potential factors, including clinicopathological features, treatment modalities, neutrophil-to-lymphocyte ratio (NLR), carbohydrate antigen (CA) 19-9 level, tumor responses correlating with overall survival (OS), local progression (LP), and distant metastases (DMs), in patients with locally advanced pancreatic cancer (LAPC) who received definitive radiotherapy (RT).MethodsWe retrospectively analyzed demographic characteristics; biologically effective doses (BED10, calculated with an α/β of 10) of RT; and clinical outcomes of 57 unresectable LAPC (all pancreatic adenocarcinoma) patients receiving definitive RT using modern techniques with and without systemic therapy between January 2009 and March 2019 at our institution. We used Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 to evaluate the radiographic tumor response after RT. The association between prognostic factors and OS was assessed using the Kaplan–Meier analysis and a Cox regression model, whereas baseline characteristics and treatment details were collected for competing-risk regression of the association with LP and DM using the Fine–Gray model.ResultsA median BED10 of 67.1 Gy resulted in a disease control rate of 87.7%, and the median OS was 11.8 months after a median follow-up of 32.1 months. The 1-year OS rate, cumulative incidences of LP, and DM were 49.2%, 38.5%, and 62.9%, respectively. Multivariate analyses showed that pre-RT NLR ≥3.5 (adjusted hazard ratio [HR] = 8.245, p < 0.001), CA19-9 reduction rate ≥50% (adjusted HR = 0.261, p = 0.005), RT without concurrent chemoradiotherapy (adjusted HR = 5.903, p = 0.004), and administration of chemotherapy after RT (adjusted HR = 0.207, p = 0.03) were independent prognostic factors for OS. Positive lymph nodal metastases (adjusted subdistribution HR [sHR] = 3.712, p = 0.003) and higher tumor reduction after RT (adjusted sHR = 0.922, p < 0.001) were significant prognostic factors for LP, whereas BED10 ≥ 67.1 Gy (adjusted sHR = 0.297, p = 0.002), CA19-9 reduction rate ≥50% (adjusted sHR = 0.334, p = 0.023), and RT alone (adjusted sHR = 2.633, p = 0.047) were significant prognostic factors for DM.ConclusionOur results indicate that pre-RT NLR and post-RT monitoring of CA19-9 and tumor size reduction can help identify whether patients belong to the good or poor prognostic group of LAPC. The incorporation of new systemic treatments during and after a higher BED10 RT dose for LAPC patients is warranted.

The exploration of quantitative intra-tumoral metabolic heterogeneity in dual-time 18F-FDG PET/CT of pancreatic cancer.

We aimed to analyze the change of quantitative intra-tumoral metabolic heterogeneity consisting of texture features and conventional metabolic parameters of pancreatic cancer (PC) in dual-time2-deoxy-2(18F) fluoro-D-glucose (18F-FDG) positron emission tomography-computed tomography (PET/CT). A retrospective analysis was conducted considering the texture features and conventional metabolic parameters in dual-time 18F-FDG PET/CT scans of PC patients. Features were extracted based on spatial distribution of 18F-FDG uptake in image. Firstly, the texture features and the conventional metabolic parameters of the delayed scan were both compared with that of the early scan. Statistically different data was defined among them. Secondly, the study evaluated the correlations between retention index (RI) of the texture features and the conventional metabolic parameters. Finally, the variation of texture features in dual-time PET/CT of resectable PC patients and unresectable PC patients was calculated separately. In total, 183 PC patients were analyzed retrospectively in this research. The conventional metabolic parameters were all statistically different between the early and delayed scans except for metabolic tumor volume (MTV). In the radiomics, there were 59 textural features. Nineteen of 59 texture features were statistically different between the early and delayed scans. Features that were more than 10% different during two scans were observed in a substantial percentage of patients. Weak correlations were only found between MTV, TLG (Total lesion glycolysis), SUVpeak and the RI of some texture features in early or delayed scans. There were obviously fewer features with significant difference in resectable PC group than in unresectable PC group. Most features showing the difference in unresectable group while no significant difference in resectable group. This study investigated thechange and inner correlations of quantitative tumoral metabolic heterogeneity in the dual-time 18F-FDG-PET/CT scan of PC patients. Some features displayed the difference between dual-time scans. Conventional metabolic parameters were weakly related to the change of texture feature. The change of texture feature in resectable PC group was different from that in unresectable PC group. This result is potential to provide more information for the image evaluation of PC.

Delta HU is a potential marker to predict chemotherapy response for unresectable pancreatic ductal adenocarcinoma

BackgroundFOLFIRINOX and gemcitabine plus albumin-bound paclitaxel (AG) regimens are recommended as first-line therapy for both locally advanced and metastatic pancreatic cancer. However, there were no specific markers to conduct personalized regimen choice. The research is to assess delta Housfield unit (delta HU), which is the difference in CT attenuation value (in HU) between enhanced and nonenhanced phase of region of interest, as a marker for predicting chemotherapy response of unresectable pancreatic cancer. MethodsA total of 179 unresectable pancreatic cancer patients were enrolled in the study. Kaplan-Meier analysis and COX regression analysis were performed for progression-free survival (PFS) and overall survival. The differences of clinical characteristics were analyzed by χ 2test. Microvessel density (MVD) was calculated by immunochemistry staining of CD34. ResultsDelta HU was an independent risk factor for unresectable pancreatic cancer (P = 0.017, HR 0.672, 95%CI 0.485–0.930). Patients with higher delta HU were associated with better PFS (P = 0.004). For modified FOLFIRINOX (mFOLFIRINOX) group, delta HU was an independent risk factor (P = 0.045, HR 0.571), but not for AG group (P = 0.473, HR 0.855). Delta HU was correlated with stroma MVD (P = 0.000, R = 0.483), not with parenchyma MVD (P = 0.074, R = 0.199). ConclusionsDelta HU was a marker predicting chemotherapy response for unresectable pancreatic cancer. Higher delta HU was associated with better survival for patients receiving mFOLFIRINOX rather than AG. The delta HU was positively correlated with stroma MVD, explaining the relationship between delta HU and prognosis.

Malnutrition, cachexia and anorexia are highly prevalent in unresectable pancreatic cancer patients

Malnutrition, cachexia and anorexia are highly prevalent in unresectable pancreatic cancer patients

Development, Validation and Comparison of Artificial Neural Network Models and Logistic Regression Models Predicting Survival of Unresectable Pancreatic Cancer.

Background: Prediction models for the overall survival of pancreatic cancer remain unsatisfactory. We aimed to explore artificial neural networks (ANNs) modeling to predict the survival of unresectable pancreatic cancer patients.Methods: Thirty-two clinical parameters were collected from 221 unresectable pancreatic cancer patients, and their prognostic ability was evaluated using univariate and multivariate logistic regression. ANN and logistic regression (LR) models were developed on a training group (168 patients), and the area under the ROC curve (AUC) was used for comparison of the ANN and LR models. The models were further tested on the testing group (53 patients), and k-statistics were used for accuracy comparison.Results: We built three ANN models, based on 3, 7, and 32 basic features, to predict 8 month survival. All 3 ANN models showed better performance, with AUCs significantly higher than those from the respective LR models (0.811 vs. 0.680, 0.844 vs. 0.722, 0.921 vs. 0.849, all p < 0.05). The ability of the ANN models to discriminate 8 month survival with higher accuracy than the respective LR models was further confirmed in 53 consecutive patients.Conclusion: We developed ANN models predicting the 8 month survival of unresectable pancreatic cancer patients. These models may help to optimize personalized patient management.

Gene expression profiling of unresectable pancreatic cancer patients treated with gemcitabine, nab-paclitaxel, metformin, and dietary supplements (DS).

736 Background: Pancreatic cancer commonly causes weight loss and many patients take supplements to improve nutrition but also for any potential anticancer properties. We conducted a pilot trial evaluating a standardized combination of dietary supplements, metformin and gemcitabine plus nab-paclitaxel chemotherapy. Methods: The supplements were custom designed by a nutritionally trained oncologist. 17 supplements were given as 12 pills and 2 smoothie packets divided twice per day. Patients began metformin on day (D)-6 to evaluate GI tolerance before starting the DS on D-3. On D1, gemcitabine and nab-paclitaxel chemotherapy was administered at standard doses. Serum samples were collected D-6, C1D1, C3D1 and at the end of treatment. RNA was extracted from PBMC samples and a total of 48 samples were analyzed from 19 patients. NanoString Human Immune Profiling and PanCancer Pathways were performed to evaluate changes in gene expression with treatment. Results: The differential expression of genes was small with dietary supplements alone and in combination with chemotherapy. After 2 months of treatment, 17 genes were upregulated while 4 genes were down regulated. At the time of tumor resistance, 33 genes were upregulated while 17 genes were downregulated. We observed downregulation of tumor suppressor gene expression with upregulation in growth factor pathways. Interestingly, SPRY2 mRNA expression was also up regulated which functions as a negative feedback regulator of multiple receptor tyrosine kinases. Conclusions: Increasing number of genes were upregulated with continued treatment. The most common pathway affected was cell cycle and apoptosis. During the initial supplement run-in period from D-6 to C1D1, IL-8 mRNA expression was upregulated the most. IL-8 is a neutrophil chemotactic factor secreted by cells involved in the innate immune response as well as pancreatic cancer cells associated with a pro-inflammatory state. Treatment with gemcitabine and nab-paclitaxel decreased the IL-8 mRNA expression. Additional studies with longer course treatment with supplements alone would be required to explore its impact on differential gene expression.

The prognostic role of soluble TGF-beta and its dynamics in unresectable pancreatic cancer treated with chemotherapy.

ObjectivesTransforming growth factor‐beta (TGF‐β) is a multifunctional regulatory factor. Here we measured serum soluble TGF‐β (sTGF‐β) levels and evaluated its dynamics and prognostic capabilities during chemotherapy in unresectable pancreatic cancer patients.MethodsWe prospectively enrolled 60 patients treated with FOLFIRINOX as the first‐line palliative chemotherapy. We collected blood samples at the time of diagnosis, first response assessment, and disease progression and measured serum sTGF‐β using an enzyme‐linked immunosorbent assay.ResultsThe patients’ median overall survival (OS) and progression‐free survival (PFS) were 10.3 (95% confidence interval [CI], 8.5‐12.1) and 6.5 (95% CI, 4.9‐8.1) months, respectively. Patients with low sTGF‐β at diagnosis (<31.2 ng/mL) had better OS and PFS than patients with high sTGF‐β, respectively, (OS, 13.7 vs 9.2 months; hazard ratio [HR], 2.602; P = .004; PFS, 9.0 vs 5.8 months; HR, 2.010; P = .034). At the time of disease progression, sTGF‐β was increased compared with that of diagnosis (mean, 26.4 vs 23.9 ng/mL). In particular, sTGF‐β was significantly increased at disease progression in patients with a partial response (mean, 25.7 vs 31.0 ng/mL; P = .049).ConclusionsPretreatment sTGF‐β levels can serve as a prognostic indicator in unresectable pancreatic cancer patients treated with FOLFIRINOX chemotherapy. Likewise, the dynamics of sTGF‐β during chemotherapy have prognostic value.

Predictors of stent occlusion in patients with unresectable pancreatic cancer after biliary metal stents.

Self-expandable metal stents (SEMS) are a widely accepted biliary endoprosthesis for patients with unresectable malignant biliary obstruction. Here, we identified predictors for the occlusion of SEMS in unresectable pancreatic cancer patients with biliary tract obstruction. Patients with a distal malignant biliary obstruction caused by unresectable pancreatic cancer who received partially covered SEMS (PC-SEMS) placement for the first time between January 2003 and January 2016 were retrospectively enrolled for analysis. The rates of PC-SEMS occlusion were evaluated. The possible predictors of PC-SEMS occlusion were analyzed using Cox regression analysis. In total, 120 patients who received PC-SEMS for unresectable pancreatic cancer were identified. The rate of PC-SEMS occlusion was 37%. The median time to occlusion of PC-SEMS was 359 days. The major causes of occlusion included biliary sludge (61%) and tumor ingrowth (30%). Cox multivariate regression analysis revealed that inadequate alkaline phosphatase/gamma-glutamyl transferase decline (defined by a decrease of <50% within 2 wk after PC-SEMS placement) was the only independent predictor of stent occlusion (hazard ratio, 2.86; 95% CI, 1.28-6.25; p = 0.01) CONCLUSION:: Inadequate alkaline phosphatase/gamma-glutamyl transferase decline is a predictor of occlusion of first-time PC-SEMS placement in unresectable pancreatic cancer patients with biliary tract obstruction.

Initial Dosimetric Outcomes and Treatment Related Toxicities Using Stereotactic MRI-Guided Radiation Therapy (SMART) for Unresectable Pancreatic Cancer at a Single Institution

High dose stereotactic body radiotherapy (SBRT) may offer improved disease outcomes for locally advanced pancreatic cancer but treatment delivery remains a challenge due to tumor proximity to organs-at-risk (OAR) and daily, anatomic variability. Stereotactic MRI-guided adaptive radiation therapy (SMART) with real-time tumor tracking allows for improved dose delivery to disease targets and OAR sparing by accounting for anatomic changes with each treatment. This study reports initial dosimetric outcomes and treatment related toxicities in unresectable pancreatic cancer patients treated using SMART. Ten patients with unresectable, locally advanced pancreatic cancer were treated on a MR-guided linear accelerator using real-time tumor tracking and motion management. A plan was generated for each patient after initial CT and MR-simulation. At each treatment, MR imaging was obtained for the daily anatomy and the initial (unadapted) plan was compared to obtain a predicted dose coverage of tumor volumes and OAR constraints using a prescribed dose of 50 Gy in 5 fractions. If OAR constraints were not met or PTV coverage was inadequate, an adaptive plan was generated based on the anatomy imaged on the day of treatment. Goal PTV coverage was 95% of the volume at 100% of prescription dose, however, this was subject to hard OAR constraints and plans were optimized for best PTV coverage within an acceptable OAR dose. For each adaptive plan generated, the delivered dose for that fraction was compared to the predicted dose from the initial plan. Only toxicities grade 3 or higher were considered for inclusion. At time of analysis, from June 2018 to February 2019, a total of 46 fractions were delivered to ten patients. Of the 46 treatments, 5 were with the initial, unadapted plan and 41 were adaptive. Due to intra-fraction adjustments that occurred during 6 treatments, only 35 adaptive plans were included for analysis. When comparing the performance of the initial plan on the daily updated MR anatomy, adaptive planning led to improved coverage of both PTV (86.36% vs. 73.15% at 100% of prescribed dose) and CTV (95.97% vs 89.59% at 95% of prescribed dose). Unadapted plans were much more likely to exceed OAR constraints, with 27 of 35 (77%) unadapted fractions predicted to violate prescribed duodenal, stomach, or small bowel constraints compared to 2 of 35 (6%) of adapted fractions. Moreover, 16/35 (46%) of unadapted fractions violated constraints for 2 of 3 abdominal OARs and 5/35 (14%) violated constraints for all 3 compared to none for adapted fractions. No grade 3 toxicities were reported in any of the treated patients. Stereotactic adaptive MRI-guided radiotherapy led to improved tumor volume coverage and reduced dose to abdominal OARs in patients with locally advanced pancreatic cancer with no grade 3 or higher toxicities. Prospective studies examining disease outcomes and treatment related toxicities are ongoing.

Neoadjuvant FOLFIRINOX versus adjuvant gemcitabine in pancreatic cancer.

4123 Background: In the metastatic or adjuvant setting for pancreatic cancer, the combination chemotherapy of fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) resulted in longer overall survival (OS) compared to gemcitabine therapy. We conducted an institutional study to compare the efficacy of neoadjuvant modified FOLFIRINOX (neo-mFOLFIRINOX) to adjuvant gemcitabine (adj-gem) for pancreatic cancer patients who completed resection. Methods: The study retrospectively enrolled patients from 2006 to 2017 from Ohio State University. While patients who received adjuvant gemcitabine were considered to be resectable upfront, patients who received neo-mFOLFIRINOX were either staged as borderline resectable (BR) or un-resectable (UR) by the institutional tumor board group. 111 patients received adj-gem (average cycles, 5.5) and 52 patients received neo-mFOLFIRINOX (average cycles, 3.5). The survival rates were determined by the Kaplan-Meier method and analyzed using Cox regression and log-rank test. Results: At a median follow up of 21.3 months, the median OS was 35.4 months in the neo-mFOLFIRINOX group and 21.8 months in the adj-gem group (hazard ratio, 0.56, 95% confidence interval (CI), 0.37-0.84 p = 0.005). The OS rate at 3 years was 46% in the neo-mFOLFIRINOX group and 22% in the adjuvant gemcitabine group (p = 0.001). The median disease free survival (DFS) was 18.6 months in the neo-mFOLFIRINOX group and 12.0 months in the adj-gem group (hazard ratio, 0.63, 95% CI, 0.43-0.93 p = 0.022). The DFS rate at 3 years was 17% in the neo-mFOLFIRINOX group and 11% in the adj-gem group (p = 0.02). On surgical pathological specimen review, the neo-mFOLFIRINOX group had statistically (p &lt; 0.05) lower tumor grade, lower rates of perineural invasion and lymphovascular invasion, lower pathological T stage, lower pathological N stage, and lower number of nodes positive compared to the adj-gem group. Frequencies of obtaining R0 resections were higher in the neo-mFOLFIRINOX versus adj-gem groups but not statistically different (51.9% vs 40.4, p = 0.2). The average age and performance status were similar between the two groups. Conclusions: At our institution, BR and UR pancreatic cancer patients who received neo-mFOLFIRINOX and completed resection had longer OS, DFS, and more favorable pathological indicators compared to those patients who had upfront surgery and adjuvant gemcitabine. Randomized clinical trials comparing neoadjuvant versus adjuvant FOLFIRINOX are needed to validate these findings.