Therapy For Advanced Pancreatic Cancer Research Articles

Feasibility and safety of endoscopic ultrasound-guided diffusing alpha emitter radiation therapy for advanced pancreatic cancer: Preliminary data

Abstract Background and study aims Pancreatic cancer is a devastating disease with limited locoregional treatment options. Diffusing alpha-emitter radiation therapy (Alpha DaRT), a novel cancer treatment using alpha-particle interstitial radiotherapy, may help address this challenge. The aim of this study was to evaluate the feasibility and safety of endoscopic ultrasound (EUS)-guided Alpha DaRT for advanced pancreatic cancer. Patients and methods Patients with inoperable locally advanced or metastatic pancreatic adenocarcinoma were treated with EUS-guided Alpha DaRT insertion. The Alpha DaRT sources were delivered into pancreatic tumors using a standard EUS needle with a novel proprietary applicator. Adverse events (AEs) were assessed based on the Common Terminology Criteria for Adverse Events version 5.0. Tumor response was evaluated by imaging 4 to 6 weeks post treatment. Results The first five patients were treated between March and September 2023. The procedure was technically successful in all cases, with Alpha DaRT sources inserted into the target tumor. Estimated gross tumor volume coverage ranged from 8% to 44%. Fourteen AEs were reported among three patients. Four were serious AEs, none of which was associated with the treatment, but rather, with disease progression or medical assistance in dying. Only two AEs (mild) were deemed possibly related to the study device. At the 35-day visit, two patients had progressive disease and three had stable disease, with one of the latter showing partial response 2 months post procedure. Conclusions Preliminary results from this first-in-human trial indicate that EUS-guided Alpha DaRT treatment for unresectable pancreatic cancer is feasible and safe, with no device-associated serious AEs. Further investigation of this promising novel modality is underway.

Effect of DeltaRex-G ± DeltaRex-G Plus (an FDA-approved drug) on advanced chemoresistant pancreatic cancer, sarcoma, and breast cancer.

e15086 Background: Expanded access for DeltaRex-G, a tumor targeted retrovector encoding a CCNG1 inhibitor, is being studied for advanced cancers. Methods: 137 archived tumor specimens were analyzed with AI RNA sequencing to identify CCNG1 expression levels, reported as: Low = 17%, Medium-low = 17%-49%, Medium-high = 50%-83%, High = 83%. Nine patients with advanced solid malignancies, whose CCNG1 levels were identified, received DeltaRex-G (2-3 x 10e11 cfu/dose one to three times a week), either without an FDA-approved drug, or with an FDA-approved drug (“DeltaRex-G Plus”). Overall survival, duration of treatment, and responses were evaluated. Results: All analyzed tumors showed enhanced CCNG1 expression. Thirty (22%) tumors exhibited High CCNG1 expression, 48 (35%) showed Medium-High CCNG1 expression, 53 (39%) displayed Medium-Low CCNG1 expression, and six (4%) had Low CCNG1 expression. One hundred (73%) patients had metastatic disease, and 37 (27%) had localized disease. There was no correlation between CCNG1 expression and disease stage. Four patients with advanced pancreatic cancer (n = 1), Stage 1 HR+Her2+ invasive breast cancer (n = 1), Stage 1 triple negative breast cancer (n = 1), and squamous cell carcinoma of skin (n = 1), received DeltaRex-G alone or DeltaRex-G Plus between 2008 and 2021 and are alive 15, 3, 2.5, and 2.5 years since treatment initiation, respectively. Retrospective analysis of their respective tumors showed CCNG1 expression levels of 24%, 23%, 74%, and 40%. Three of the patients are in sustained remission and the patient with squamous cell carcinoma had a partial response. Of the five patients currently being treated with DeltaRex-G Plus: one patient with advanced breast cancer had a partial response (n = 1), one patient with advanced pancreatic cancer (n = 1) and three patients with soft tissue sarcoma (n = 3) had stable disease. Four of five patients had previously progressed with standard doses of chemotherapy. All patients are alive from 11 to 22 weeks since treatment initiation. No serious treatment-related adverse events have been reported. Conclusions: Taken together, the data shows that (1) 100% of 137 tumors tested have enhanced CCNG1 expression, further reinforcing the 2021 FDA-CBER authorization for use of DeltaRex-Plus, and (2) DeltaRex-G Plus is a promising therapy for advanced pancreatic cancer, sarcoma, and breast cancer. Randomized Phase 2/3 studies are warranted to confirm the efficacy and safety of DeltaRex-G Plus. Clinical trial information: NCT04091295 .

Second-line chemotherapy in elderly patients with advanced pancreatic cancer: A mono-institutional retrospective experience.

606 Background: Only few randomized clinical trials have been conducted for second line therapy in advanced pancreatic cancer (APC). In these studies, elderly patients are poorly represented, even if the median age at diagnosis of APC is increasing; therefore, limited efficacy and safety data are available. Here, we present a retrospective monocentric analysis of second line chemotherapy in elderly patients treated at our Hospital. Methods: This study included patients with APC and aged>70 years old receiving a second-line chemotherapy for APC at our institution from March 2015 to August 2020. The primary endpoints were progression-free survival to second line (PFS2) and overall survival (OS); the secondary endpoint was safety. The Kaplan–Meier method was used to estimate efficacy outcome; log-rank test and Cox-regression model were used to compare the differences, considering a statistically significant p value < 0.05. Results: 169 pts affected with APC received first-line chemotherapy and 61 of them (36%) received second-line therapy. The median age at diagnosis was 74 Years (70-83), 31 (50%) were female; ECOG PS was 0-1 in 44 pts (59%), 41% had at least 2 comorbidities. The regimens of chemotherapy used were: mFOLFOX (28; 46%), Gemcitabine (11; 18%), Capecitabine (15; 24.6%), FOLFIRI (6; 9.8%), mFOLFIRINOX (1; 1.6%). 4 pts (6.6%) had a partial response and 22 (36.1%) had a stable disease, with a disease control rate of 42.7%. The median follow-up was 22.8 months; median PFS2 was 4.5 months (IC 95%: 2.5-6.5) and median OS was 15.4 months (IC 95%: 7.2-23.6). At the univariable analysis, there was a statistically significant difference in mPFS2 according to ECOG PS (0-1 vs 2: 5.3 [IC 95%: 3.5-7.0] vs 2.2 [IC 95%: 1.2-5.4] months; p 0.02) and number of metastatic sites at the beginning of second line therapy (1 vs 2 or more: 5.8 [IC 95%: 4.8-6.7] vs 3.4 [IC 95%: 3.1-3.8] months; p 0.006). At the multivariable analysis, both number of metastatic sites and ECOG PS were confirmed associated with mPFS2. Number of metastatic sites and ECOG PS were both also associated with mOS. No unexpected adverse events were reported, and no patients had to interrupt treatment due to toxicity. Conclusions: In our experience, only about a third of elderly pts with APC received second-line therapy; in these patients, ECOG PS, disease’s burden and the response to therapy are all positive prognostic factors. With regard to the safety profile, older age does not seem to negatively increase serious toxicities. In conclusion, elderly pts should not be precluded from an active treatment (also in later lines setting) and careful patients selection should guide treatment indication.

Efficacy of first-line combination therapies versus gemcitabine monotherapy for advanced pancreatic cancer: a systematic review and network meta-analysis.

Various first-line gemcitabine-based or fluorouracil-based combination regimens were approved in patients with advanced pancreatic cancer. Recent randomized clinical trials (RCTs) have investigated chemotherapy backbones in combination with novel investigational drugs, including chemotherapy agents or targeted drugs. However, the comparative efficacy of these different combination therapies remains limited. This systematic review and network meta-analysis aimed to assess the efficacy of first-line combination therapies for advanced pancreatic cancer. The study included 46 RCTs with 10,499 patients and 47 distinct regimens, using data sources from MEDLINE, EMBASE, Cochrane Clinical Trials, and ClinicalTrials.gov from January 1, 2010 to April 23, 2024. The primary outcomes were overall survival (OS) and progression-free survival (PFS), while secondary outcomes included overall response rate (ORR) and disease control rate (DCR). The analysis revealed that gemcitabine+nab-paclitaxel (GA), GA with platinum and fluorouracil (GA+Plat+FU), gemcitabine with fluorouracil (G+FU), G+Plt+FU, and FOLFIRINOX were associated with superior OS and PFS compared to gemcitabine monotherapy. Triplet or quadruplet polychemotherapy combinations, such as GA+Plat+FU, G+Plt+FU, and FOLFIRINOX, demonstrated better OS benefit with hazard ratios of 0.42 (95% CI, 0.26-0.68), 0.41 (95% CI, 0.24-0.71), and 0.58 (95% CI, 0.48-0.71), respectively, compared to doublet regimens like GA and G+FU, which had hazard ratios of 0.70 (95% CI, 0.59-0.82) and 0.82 (95% CI, 0.72-0.95), respectively. Notably, no targeted drugs, monoclonal antibodies, or other medications showed improved survival when added to chemotherapy backbones. These findings support the use of gemcitabine-based or fluorouracil-based triplet or quadruplet regimens for better survival outcomes in patients with advanced pancreatic cancer. Further research is warranted to explore the potential benefits of adding chemotherapy agents, such as fluorouracil, to the GA doublet regimen.

Genomic Predictors Associated With Exceptional Response to Systemic Therapy in Advanced Pancreatic Cancer.

Exceptional response to therapy is rare in patients with advanced pancreatic cancer. This study explored potential genomic differences between typical and exceptional responses that could confer more favorable biology. We included exceptional responders and controls with advanced pancreatic cancer from Cleveland Clinic from April 2013 to August 2017. Exceptional responders were defined as patients with an overall survival of more than 18 months for metastatic disease and more than 24 months for locally advanced disease. Clinical data were obtained, and next-generation sequencing was performed. Statistical analyses comparing the 2 groups were performed using descriptive statistics, the Kaplan-Meier method, and the log-rank test. The study comprised 4 exceptional responders and 6 controls. Both groups were well balanced in age, sex, race, and treatment regimens. Exceptional responders had significantly fewer nonsynonymous mutations than controls (2.25 vs 5.17; P = .014). A mutation count of less than 3 was associated with significantly better progression-free survival (17.2 vs 2.3 months; P = .002) and overall survival (29.4 vs 4.6 months; P = .013). Tumor mutational burden did not differ between exceptional responders and controls (4.88 vs 5.70 mut/Mb; P = .39). A lower number of nonsynonymous mutations may correlate with exceptional outcomes in patients with pancreatic cancer. These findings should encourage future studies into genomic signatures of exceptional response.

FOLFOX regimen after failure of fluorouracil and leucovorin plus nanoliposomal-irinotecan therapy for advanced pancreatic cancer: a retrospective observational study

BackgroundFluorouracil, leucovorin (5FU/LV), and nanoliposomal-irinotecan (nal-IRI) combination therapy has been established as the second-line treatment for advanced pancreatic ductal adenocarcinoma. Oxaliplatin with 5FU/LV (FOLFOX) is often used as a subsequent treatment, although its efficacy and safety are yet to be fully elucidated. We aimed to evaluate the efficacy and safety of FOLFOX as a third- or later-line treatment for patients with advanced pancreatic ductal adenocarcinoma.MethodsWe conducted a single-centre, retrospective study that enrolled 43 patients who received FOLFOX after failure of gemcitabine-based regimen followed by 5FU/LV + nal-IRI therapy between October 2020 and January 2022. FOLFOX therapy consisted of oxaliplatin (85 mg/m2), levo-leucovorin calcium (200 mg/m2) and 5-FU (2400 mg/m2) every 2 weeks per cycle. Overall survival, progression-free survival, objective response, and adverse events were evaluated.ResultsAt the median follow-up time of 3.9 months in all patients, the median overall survival and progression-free survival were 3.9 months (95% confidence interval [CI], 3.1–4.8) and 1.3 months (95% CI, 1.0–1.5), respectively. Response and disease control rates were 0 and 25.6%, respectively. The most common adverse event was anaemia in all grades followed by anorexia; the incidence of anorexia and grades 3 and 4 was 21 and 4.7%, respectively. Notably, grades 3–4 peripheral sensory neuropathy was not observed. Multivariable analysis revealed that a C-reactive protein (CRP) level of > 1.0 mg/dL was a poor prognostic factor for both progression-free survival and overall survival: hazard ratios were 2.037 (95% CI, 1.010–4.107; p = 0.047) and 2.471 (95% CI, 1.063–5.745; p = 0.036), respectively.ConclusionFOLFOX as a subsequent treatment after failure of second-line treatment with 5FU/LV + nal-IRI is tolerable, although its efficacy is limited, particularly in patients with high CRP levels.

Effect of pancreatic enzyme replacement therapy (PERT) on body weight in advanced pancreatic cancer (APC).

698 Background: Malnutrition/cachexia is common in PC and is associated with multiple adverse patient (pt) outcomes. Current NCCN guidelines recommend PERT in PC pts with exocrine pancreatic insufficiency (EPI). However, little evidence exists regarding the impact of PERT on clinical outcomes in PC, especially APC. Data on impact of PERT use on change in body weight is presented here. Methods: Pts in this retrospective cohort study were identified from the Virginia Mason PC database. Eligibility requirements included: 1) no upfront resection 2) no prior PC therapy 3) pancreatic stool elastase 1< 200 µg/g stool or documented clinical evidence of EPI at diagnosis 4) treatment at least to initial restaging event (8 weeks) 5) available data regarding PERT use/dosage. Weight/BMI was assessed at baseline and after 8 weeks on therapy. Two pt groups were compared; a) pts prescribed PERT for EPI at recommended package insert dose (≥ 500KU-2500/kg/meal for ≥ 3 meals/day) for ≥ 50% treatment period and b) pts who received no PERT. Pts on PERT at lower than recommended dose and /or < 50% interval between 1st treatment and reassessment were excluded from analysis. Statistical significance was determined using the T-test for continuous variables, chi-squared for categorical variables. Results: 505 total pts were study eligible; 197 (39%) pts received PERT, 308 (61%) pts did not. Pt characteristics are shown. Despite a more adverse patient population with respect to weight loss, pts receiving PERT after 8 weeks experienced less change in weight (-0.36 kg vs -1.54 kg, P = 0.025) and change in BMI ( -0.64% vs -1.96., p= 0.026). Pts with cachexia experienced a similar outcome (-0.36% vs. -2.02 %, p= 0.026). No other pt characteristics achieved statistical significance. Conclusions: Despite a more adverse population with respect to weight loss at baseline, PERT usage prescribed per package insert guidance reduced wt loss/ change in BMI loss in APC over the 1st 8 weeks of therapy. This was also true in APC pts with cachexia. Further analysis of the impact of PERT therapy in APC with respect to treatment tolerability, and toxicity, quality of life and overall survival is warranted. [Table: see text]

Personalized matched targeted therapy in advanced pancreatic cancer: a pilot cohort analysis

Despite progress, 2-year pancreatic cancer survival remains dismal. We evaluated a biomarker-driven, combination/N-of-one strategy in 18 patients (advanced/metastatic pancreatic cancer) (from Molecular Tumor Board). Targeted agents administered/patient = 2.5 (median) (range, 1–4); first-line therapy (N = 5); second line, (N = 13). Comparing patients (high versus low degrees of matching) (matching score ≥50% versus <50%; reflecting number of alterations matched to targeted agents divided by number of pathogenic alterations), survival was significantly longer (hazard ratio [HR] 0.24 (95% confidence interval [CI], 0.078–0.76, P = 0.016); clinical benefit rates (CBR) (stable disease ≥6 months/partial/complete response) trended higher (45.5 vs 0.0%, P = 0.10); progression-free survival, HR, 95% CI, 0.36 (0.12–1.10) (p = 0.075). First versus ≥2nd-line therapy had higher CBRs (80.0 vs 7.7%, P = 0.008). No grade 3–4 toxicities occurred. The longest responder achieved partial remission (17.5 months) by co-targeting MEK and CDK4/6 alterations (chemotherapy-free). Therefore, genomically matched targeted agent combinations were active in these advanced pancreatic cancers. Larger prospective trials are warranted.

ChemoSensitivity Assay Guided Metronomic Chemotherapy Is Safe and Effective for Treating Advanced Pancreatic Cancer.

Simple SummaryInnovative chemotherapy regimens and tools to guide therapy in advanced pancreatic cancer are greatly needed. We present results of a study combining an innovative, metronomic chemotherapy strategy together with a blood-based pharmacogenomic tool to guide effective drug therapy. This study provides proof of principle that guided, metronomic chemotherapy for treatment of pancreatic cancer is a promising approach.Cytotoxic chemotherapy remains the mainstay of treatment for advanced pancreatic adenocarcinoma (PDAC). Emerging studies support metronomic chemotherapy (MCT) as effective, challenging established paradigms of dosing and schedules. The blood-based ChemoSensitivity Assay has been shown to predict response and survival in advanced PDAC patients treated with standard chemotherapy. The current study combines these concepts for a highly personalized treatment approach. This was a retrospective analysis; a pilot (n = 50) and validation cohort (n = 45) were studied. The ChemoSensitivity Assay was performed at baseline and during therapy; results were correlated to drugs administered and patient outcomes. MCT was administered based on the assay results at the treating physician′s discretion. Patients in the pilot cohort experienced favorable survival compared with historical controls (median overall survival (mOS) 16.8 mo). Patients whose treatment closely matched the ChemoSensitivity Assay predictions experienced longer median time on lines of therapy (5.3 vs. 3.3 mo, p = 0.02) and showed a trend for longer mOS (20.9 vs. 12.5 mo, p = 0.055) compared with those not closely matched. These findings were confirmed in the validation cohort. Overall, patients treated with MCT closely matching Assay results experienced a remarkable mOS of 27.7 mo. ChemoSensitivity profiling-guided MCT is a promising approach for personalized therapy in advanced PDAC.

Contrast-enhanced ultrasound for evaluating response to pulsed-wave high-intensity focused ultrasound therapy in advanced pancreatic cancer.

To examine whether contrast-enhanced ultrasound (CEUS) parameters in patients with advanced pancreatic cancer could be used to assess response to treatment with pulsed-wave high intensity focused ultrasound (PW-HIFU). We prospectively recorded the pretreatment and posttreatment CEUS related parameters, CA19-9, pain scores of 30 patients with advanced pancreatic cancer treated with PW-HIFU treatment. Correlation of clinical parameters, tumor characteristics, and PW-HIFU treatment energy with CEUS parameters were analyzed. Pain score decreased after treatment (from 4.80±2.14 to 3.28±1.93, p = 0.001). CA19-9 dropped in RT decreased group, 4 weeks after one session PW-HIFU, compared with prolonged group (p = 0.013). According to the display of blood vessels in the mass by CEUS, tumors were classified by vessel grade (VG), VG1: no vessel can be seen; VG 2: vessels diameter < 5 mm; VG 3: vessels diameter > 5 mm. VGs were different between increased and decreased relative rise intensity (rRI) groups (p = 0.008). VG1 group shown a decreased rRI after treatment, while VG3 group showed the opposite trend (p = 0.006). CEUS can evaluating response to PW-HIFU in advanced pancreatic cancer. Quantitative analysis may help to assess the short-term efficacy of patients and help for individualized treatment.

FOLFIRINOX as First-line Chemotherapy in Japanese Patients Suffering from Metastatic Pancreatic Cancer (KOBE FOLFIRINOX Study)

Background/Aim: FOLFIRINOX (oxaliplatin, irinotecan, 5-fluorouracil, and leucovorin) combination chemotherapy is the gold-standard therapy for advanced pancreatic cancer. In this study, FOLFIRINOX dosages for Japanese patients were established enabling FOLFIRINOX therapy optimization for efficient use. Patients and Methods: Patients with advanced pancreatic cancer were treated with varying doses of FOLFIRINOX to determine the optimum dosage for highest remission outcomes with the least post-chemotherapy toxicities. Results: Patients given 180 mg of irinotecan and a 400 mg bolus of 5-fluorouracil (5-FU) showed a marked difference in outcome when compared to irinotecan 180 mg given without the 5-FU bolus, with the overall response rate being 28%, a survival time of 6.4 months and progression-free survival time of 4.5 months. Conclusion: The optimum dose of FOLFIRINOX was a dosage combination of oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, l-leucovorin 400 mg/m2 and 5-FU 2,400 mg/m2, administered as a continuous 46-h infusion.

Clinical Impact of Molecular Subtyping of Pancreatic Cancer.

Pancreatic ductal adenocarcinoma is a highly lethal malignancy, which has now become the seventh most common cause of cancer death in the world, with the highest mortality rates in Europe and North America. In the past 30 years, there has been some progress in 5-year survival (rates increasing from 2.5 to 10%), but this is still extremely poor compared to all other common cancer types. Targeted therapies for advanced pancreatic cancer based on actionable mutations have been disappointing, with only 3–5% showing even a short clinical benefit. There is, however, a molecular diversity beyond mutations in genes responsible for producing classical canonical signaling pathways. Pancreatic cancer is almost unique in promoting an excess production of other components of the stroma, resulting in a complex tumor microenvironment that contributes to tumor development, progression, and response to treatment. Various transcriptional subtypes have also been described. Most notably, there is a strong alignment between the Classical/Pancreatic progenitor and Quasi-mesenchymal/Basal-like/Squamous subtype signatures of Moffit, Collinson, Bailey, Puleo, and Chan-Seng-Yue, which have potential clinical impact. Sequencing of epithelial cell populations enriched by laser capture microscopy combined with single-cell RNA sequencing has revealed the potential genomic evolution of pancreatic cancer as being a consequence of a gene expression continuum from mixed Basal-like and Classical cell populations within the same tumor, linked to allelic imbalances in mutant KRAS, with metastatic tumors being more copy number-unstable compared to primary tumors. The Basal-like subtype appears more chemoresistant with reduced survival compared to the Classical subtype. Chemotherapy and/or chemoradiation will also enrich the Basal-like subtype. Squamous/Basal-like programs facilitate immune infiltration compared with the Classical-like programs. The immune infiltrates associated with Basal and Classical type cells are distinct, potentially opening the door to differential strategies. Single-cell and spatial transcriptomics will now allow single cell profiling of tumor and resident immune cell populations that may further advance subtyping. Multiple clinical trials have been launched based on transcriptomic response signatures and molecular subtyping including COMPASS, Precision Promise, ESPAC6/7, PREDICT-PACA, and PASS1. We review several approaches to explore the clinical relevance of molecular profiling to provide optimal bench-to-beside translation with clinical impact.

Rucaparib is a safe and effective maintenance therapy for advanced pancreatic cancer

Select patients with advanced pancreatic cancer may have another effective treatment option for maintenance therapy. New data show that rucaparib is effective in stopping tumor growth or substantially shrinking tumors in the majority of patients with select biomarkers enrolled in a phase II trial by researchers at the Abramson Cancer Center at the University of Pennsylvania in Philadelphia.1 The open-label, single-arm, single-stage, phase II study was conducted to test the hypothesis that rucaparib, a poly(adenosine diphosphate ribose) polymerase inhibitor (PARPi), would confer at least 60% progression-free survival at 6 months as maintenance therapy in patients with platinum-sensitive advanced pancreatic cancer with select biomarkers. The study included 46 patients with locally advanced or metastatic pancreatic cancer with confirmed or likely pathogenic germline or somatic pathogenic variants in BRCA1, BRCA2, or PALB2 genes. Patients were aged at least 18 years and had received prior treatment with platinum-based chemotherapy; 34 patients received at least 16 weeks or more, whereas 8 patients received less than 16 weeks. All patients were treated with rucaparib at a dose of 600 mg delivered orally twice a day during every day of a 28-day cycle until disease progression or unacceptable toxicity. For the 42 patients available for evaluation, the progression-free survival rate at 6 months was 59.5%, and the median progression-free survival was 13.1 months. When disease control was examined, 41.7% of the patients, including 3 of 6 patients with the variant PALB2 and 1 of 2 patients with a somatic BRCA2 mutation, experienced either a complete response or a partial response. Kim A. Reiss, MD, assistant professor at the Abramson Cancer Center and lead author of the study, says that these findings expand on prior results from the phase III POLO study showing the efficacy of maintenance olaparib, the first poly(adenosine diphosphate ribose) polymerase 1 (PARP1) agent to be used as maintenance therapy for advanced pancreatic cancer, in select patients with germline BRCA mutations and platinum-sensitive metastatic pancreatic cancer.2 “Our study showed efficacy in patients with additional variants,” she says. “The role of maintenance PARP inhibition may possibly be expanded to patients with germline PALB2 mutations and those with somatic BRCA mutations.” Dr. Reiss also notes the efficacy of rucaparib for patients with locally advanced disease and patients who did not receive a full 4 months of prior platinum therapy. “Although platinum sensitivity is key for PARPi efficacy, a full 4 months of treatment may not be required prior to switching to maintenance therapy,” she says. This finding is important because of toxicities of platinum-based chemotherapy that typically emerge before the completion of 16 weeks of therapy.

Meta-analysis and indirect treatment comparison of modified FOLFIRINOX and gemcitabine plus nab-paclitaxel as first-line chemotherapy in advanced pancreatic cancer

BackgroundModified FOLFIRINOX and gemcitabine plus nab-paclitaxel (GEM-NAB) have been recommended as first-line therapies for advanced pancreatic cancer (PC). Due to the lack of evidence to directly compare them, we conducted this network meta-analysis to indirectly compare the effectiveness and toxicity of modified FOLFIRINOX and GEM-NAB.MethodsThe eligible retrospective studies on treatments related to modified FOLFIRINOX and GEM-NAB up to 4 April 2020 were searched and assessed. We used the frequentist model to analyze the survival and toxicity data between different treatments. Pooled analysis for overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and events of toxicity were analyzed in this study.ResultsTwenty-two studies were involved in this network meta-analysis. The comparisons on OS and PFS showed that modified FOLFIRINOX and GEM-NAB had similar treatment efficacy (OS: 1.13; 95% CI: 0.78–1.63; PFS: HR: 1.19; 95% CI: 0.85–1.67). GEM-NAB was more effective than modified FOLFIRINOX based on the result of ORR (RR: 1.43; 95% CI: 1.04–1.96). Moreover, our analysis showed a similar toxicity profile between modified FOLFIRINOX and GEM-NAB.ConclusionsThe current evidence showed that modified FOLFIRINOX and GEM-NAB were similar in survival and toxicity. Many factors should be considered for in the formulation of optimal treatment, and our meta-analysis could provide some guidance to treatment selection in the first-line setting for advanced PC.

Anti-PD-1 antibody combined with albumin-bound paclitaxel and gemcitabine (AG) as first-line therapy and Anti-PD-1 monotherapy as maintenance in metastatic pancreatic ductal adenocarcinoma (PDAC).

e16218 Background: Two studies in ASCO 2018 showed the preliminary efficacy of PD-1 inhibitor and AG as first-line therapy for advanced pancreatic cancer, the disease control rate (DCR) was up to 100%. However, in a phase 1 study of nivolumab plus nab-paclitaxel and gemcitabine in advanced PDAC, the objective response rate (ORR) was only 18%, and the progression-free survival (PFS)/overall survival (OS) were 5.5/9.9 months, which was quite different from what had been reported before in ASCO. All the patients received continuous chemotherapy, and the tolerance was poor. Recently, maintenance therapy on pancreatic cancer was widely investigated in clinical trials. The present study explored the camrelizumab (anti-PD-1 antibody) combined with AG as the first-line treatment, and camrelizumab as maintenance therapy for metastatic PDAC (mPDAC) among Chinese patients. Methods: In this single-arm, single-center, exploratory study, patients who were pathologically or cytologically diagnosed as mPDAC and had not received systemic treatment before, with an ECOG performance status of 0-1 would receive: albumin-bound paclitaxel 125 mg/m2 plus gemcitabine 1000 mg/m2 (days 1, 8), and camrelizumab, 200mg (day 1) for a 21-day cycle. After six cycles, if there was no evidence of disease progression, camrelizumab (200mg, every 21 days) monotherapy as maintenance therapy would be given. Primary endpoint was ORR assessed according to RECIST 1.1. The secondary endpoint was DCR, PFS, OS, etc. Safety was also assessed. Results: From July 3, 2019 to July 1, 2020, twenty patients were enrolled and received the study treatment. The median age was 63 years (range 33-78). Sixteen participants (80%) were male. Eleven patients (55%) received six cycles of camrelizumab combined with AG and subsequential maintenance therapy. Nineteen patients received at least one imaging evaluation, one patient (5%) achieved complete response, eleven (55%) patients achieved partial response, five (25%) patients were assessed as stable disease, and progressive disease was observed in two patients (10%) who died within 2 months. The ORR (primary endpoint) and DCR were 60% and 85%, respectively. The data of PFS and OS were immature. The most common AEs (all grade, grade≥3) were erythropenia (55%, 0%), leukopenia (45%, 10%), neutropenia (40%, 15%), anemia (30%, 5%), thrombocytopenia (30%, 5%). One patient received day 1 camrelizumab plus AG, and the day 8 therapy was skipped due to thrombocytopenia. During the second cycle, he presented with jaundice due to disease progression and died rapidly. Conclusions: The ORR and DCR of chemotherapy-naive mPDAC patients receiving camrelizumab plus AG were high. Safety findings were consistent with previous data observed from camrelizumab or AG treatment; with no unexpected safety signals. Clinical trial information: NCT04181645.

α1,6-Fucosyltransferase contributes to cell migration and proliferation as well as to cancer stemness features in pancreatic carcinoma

BackgroundPancreatic carcinoma is one of the deadliest malignant diseases, in which the increased expression of α1,6-fucosyltransferase (FUT8), a sole enzyme responsible for catalyzing core fucosylation, has been reported. However, its pathological roles and regulatory mechanisms remain largely unknown. Here, we use two pancreatic adenocarcinoma cell lines, MIA PaCa-2 and PANC-1 cells, as cell models, to explore the relationship of FUT8 with the malignant transformation of PDAC. MethodsFUT8 knockout (FUT8-KO) cells were established by the CRISPR/Cas9 system. Cell migration was analyzed by transwell and wound-healing assays. Cell proliferation was examined by MTT and colony-formation assays. Cancer stemness markers and spheroid formations were used to analyzed cancer stemness features. ResultsDeficiency of FUT8 inhibited cell migration and proliferation in both MIA PaCa-2 and PANC-1 cells compared with wild-type cells. Moreover, the expression levels of cancer stemness markers such as EpCAM, CXCR4, c-Met, and CD133 were decreased in the FUT8-KO cells compared with wild-type cells. Also, the spheroid formations in the KO cells were loose and unstable, which could be reversed by restoration with FUT8 gene in the KO cells. Additionally, FUT8-KO increased the chemosensitivity to gemcitabine, which is the first-line therapy for advanced pancreatic cancer. ConclusionsFUT8-KO reduced the cell proliferation and migration. Our results are the first to suggest that the expression of FUT8 is involved in regulating the stemness features of pancreatic cancer cells. General significanceFUT8 could provide novel insights for the treatment of pancreatic carcinoma.

AGIG chemo-immunotherapy in patients with advanced pancreatic cancer: A single-arm, single-center, phase II study.

384 Background: To date, chemotherapy remains the only effective treatment of unresectable pancreatic adenocarcinoma. In the last few years, the interest in the use of immunological anticancer strategies is greatly increased. AGIG is a novel chemo-immunotherapy regimen that combines nab-paclitaxel + gemcitabine chemotherapy with sequential recombinant interleukin-2 and granulocyte-macrophage colony stimulating factor (GM-CSF) therapy. We conducted a single-arm prospective phase II study to determine the efficacy and safety of the first-line treatment of advanced pancreatic cancer with AGIG regimen. Methods: Nab-paclitaxel (120 mg/m2) and gemcitabine (1000 mg/m2) were administered intravenously to all patients on days 1 and 8 triweekly, interleukin-2 and GM-CSF (100 µg) were administered subcutaneously on days 3-5 after chemotherapy. The primary end point was ORR by the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points included safety profile, progression-free survival (PFS), overall survival (OS). Patients’ conditions and the efficacy and safety were assessed every 4 cycles. Results: Between 11/2018 and 01/2020, 64 patients were enrolled. In the 64 evaluable patients, the ORR and DCR were 43.75% and 76.6%, respectively. The median follow-up time was 12.1 (range 7.1–22.4) months, the median PFS was 5.7 (range 1.63–15.8) months, and the median OS was 14.2 (range 2.9–22.0) months. The most common adverse event was fever (75%). The incidence of grade 3/4 neutropenia was 4.69%. In subgroup analyses, we found that eosinophil count in the blood elevated three times higher than baseline level predicted a longer survival. Conclusions: The AGIG Chemo-immunotherapy regimen has presented encouraging ORR, OS, and manageable toxicities as first-line therapy for advanced pancreatic cancer. This regimen may be a novel reliable therapeutic option for patients with preserved performance status. The improvement of treatment efficiency may be related to the activation of non-specific immune response. Clinical trial information: NCT0376867. Research Sponsor: The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School. [Table: see text]

Antitumor effect of humanized anti‑tissue factor antibody‑drug conjugate in a model of peritoneal disseminated pancreatic cancer.

Tissue factor(TF) is an attractive target for cancer therapy due to its overexpression in multiple types of malignancies. In addition, TF has been reported to play functional roles in both cancer development and metastasis. Several groups have already developed antibody‑drug conjugates(ADCs) against TF for use as cancer treatments, and have demonstrated their efficacies in conventional subcutaneous xenograft models and patient‑derived xenograft models. However, no previous studies have investigated the effectiveness of anti‑TF ADC in an advanced‑stage cancer model. The present study developed an original humanized anti‑TF monoclonal antibody conjugated with monomethyl auristatin E, and evaluated its invivo efficacy in a pancreatic cancer xenograft model with peritoneal dissemination. Invitro assays demonstrated that the anti‑TF ADC had potent binding affinity and cytotoxic activity against human pancreatic cancer cells that strongly expressed TF antigens. The anti‑TF ADC also exhibited greater antitumor effect than that of a control ADC in conventional subcutaneous xenograft models, with efficacy depending on the TF expression in the tumor tissues. Furthermore, the anti‑TF ADC significantly inhibited tumor growth in an orthotopic xenograft model, and extended the survival period in a murine peritoneal dissemination model. These results indicated that anti‑TF ADC has the potential to be an effective treatment not only for primary tumors, but also for those that are widely disseminated. Therefore, it can be concluded that ADC targeting TF may be a promising agent for advanced pancreatic cancer therapy.

Pancreatic exocrine insufficiency and pancreatic enzyme replacement therapy in patients with advanced pancreatic cancer: A systematic review and meta-analysis.

Pancreatic cancer is the fourth leading cause of cancer mortality. Most patients are diagnosed with advanced pancreatic cancer, either at locally advanced or metastatic stages, and have a high rate of malnutrition and weight loss which are associated with poor outcomes. Pancreatic exocrine insufficiency is one of the causes of malnutrition and weight loss in these patients. The prevalence and clinical consequences of pancreatic exocrine insufficiency in advanced pancreatic cancer are poorly investigated with heterogeneous results. We sought to determine the prevalence and clinical consequences of pancreatic exocrine insufficiency and the effect of pancreatic enzyme replacement therapy in patients with advanced pancreatic cancer by systematic review and meta-analysis. Scopus, Medline, and Embase were searched for cohort studies or randomised clinical trials reporting pancreatic exocrine insufficiency and/or the effect of pancreatic enzyme replacement therapy in patients with advanced pancreatic cancer. We considered pancreatic exocrine insufficiency as an abnormal result on direct and/or indirect pancreatic exocrine function tests. Pancreatic enzyme replacement therapy was evaluated by its effect on survival and quality of life in patients with advanced pancreatic cancer. A total of 11 studies were included; seven studies reported the prevalence of pancreatic exocrine insufficiency and seven the effect of pancreatic enzyme replacement therapy in advanced pancreatic cancer. The pooled prevalence of pancreatic exocrine insufficiency in advanced pancreatic cancer was 72% (95% confidence interval: 55-86%), being significantly higher when tumours were located in the pancreatic head (relative risk = 3.36, 1.07-10.54; p = 0.04) six studies investigated the impact of pancreatic enzyme replacement therapy on survival/quality of life. Pancreatic enzyme replacement therapy was associated with 3.8 months (95% confidence interval: 1.37-6.19) survival benefit. Patients receiving pancreatic enzyme replacement therapy had a trend towards a better quality of life.Conclusions The prevalence of pancreatic exocrine insufficiency in advanced pancreatic cancer is substantial and its treatment can improve the outcomes of these patients.

Integrative therapy for advanced pancreatic cancer using Kampo and western medicine: A case report

A 45-year-old male patient diagnosed as stage IVa pancreatic cancer received anti-cancer treatment with chemotherapy and radiotherapy. During the treatment, he complained of nausea, appetite loss, and fatigue. He received a Kampo diagnosis of qi deficiency, blood stasis, and heat with phlegm; consequently, qi supplementation, smoothing blood, and relieving fever were initiated using Juzentaihoto and Keppuchikuoto. After this treatment, the symptoms showed remarkable improvement. However, computed tomography revealed multiple lung nodules. We prescribed crude drugs with anti-cancer effects, including Scutellaria barbata and Oldenlandia diffusa. These drugs led to slowed development of lung metastases that could be surgically resected. He survived for 7 years after the advanced diagnosis without loss of quality of life. Kampo medicine may be useful for disease control and supportive care in advanced pancreatic cancer patients.