Chemotherapy For Advanced Pancreatic Cancer Research Articles

Dose optimization of pancreatic enzyme replacement therapy is essential to mitigate muscle loss in patients with advanced pancreatic cancer and exocrine pancreatic insufficiency

Background & AimsExocrine pancreatic insufficiency (EPI) contributes to malnutrition, marked by muscle loss during chemotherapy for advanced pancreatic cancer (aPC). Pancreatic enzyme replacement therapy (PERT) is recommended for patients with EPI; however, it’s efficacy for attenuating muscle loss has not been demonstrated. We aimed to delineate the impact of PERT dose on muscle loss using a 7-year population-based cohort with aPC who were provided PERT at the discretion of their oncologist or dietitian according to clinical indications of EPI. MethodsAll patients treated with chemotherapy for aPC from 2013-2019 in Alberta, Canada (population ∼4.3 million) were included if they had computed tomography (CT) scans both prior to and 12 ± 4 weeks after chemotherapy initiation. Change in muscle area (cm2) was measured at 3rd lumbar level on repeated CT scans. Muscle loss was defined by measurement error (loss >2.3 cm2). Clinical and pharmaceutical data were retrieved from provincial registries. For patients who were dispensed PERT -8 to +6 weeks from chemo start (PERT users), estimated dose consumed per day was calculated as: (total dose dispensed)/(days, first to last dispensation). PERT users were categorized as high dose or low dose users according to the median estimated dose consumed. Non-users were classified as No PERT. Association between PERT use and muscle loss was analyzed with multivariable logistic regression. ResultsAmong 210 patients, 81 (39%) were PERT users. Median estimated dose consumed per day of 75 000 USP lipase units defined the cutoff between low dose and high dose uses. There were no significant differences in baseline characteristics between high dose and low dose groups. Muscle loss was more prevalent among low dose compared to both high dose and No PERT groups (88% vs. 58% and 67%, p < .05). In the multivariable model predicting muscle loss, low dose PERT was independently associated with greater odds of muscle loss (OR 5.4, p=.004) vs. high dose, independent of tumour response, disease stage, and chemotherapy regimen. ConclusionIn patients with clinical indications of EPI during chemotherapy for aPC, low doses of PERT were insufficient to prevent muscle loss. Patients with EPI consuming higher doses of PERT had similar odds of muscle maintenance to patients without clinical indications of EPI. Provider education for optimal PERT dosing in patients with EPI should be prioritized, and resources must be allocated to support dose titration.

The efficacy of coaxial percutaneous iodine-125 seed implantation combined with arterial infusion chemotherapy for advanced pancreatic cancer: a randomized clinical trial

Background This study aimed to evaluate the clinical efficacy of coaxial percutaneous Iodine-125 (125I) seed implantation in combination with arterial infusion chemotherapy for the treatment of advanced pancreatic cancer (PC) through a randomized controlled trial. Methods A total of 101 patients with advanced PC were randomized into two groups: control group treated with systemic intravenous chemotherapy and experimental group that received 125I seed implantation in combination with arterial infusion chemotherapy. Outcomes, including tumor control, abdominal pain relief, and survival time were compared between these two groups (Trial Registration No. KYKT2018-65). Results Pretreatment abdominal pain scores were comparable between the two groups, whereas the abdominal pain scores at 1- and 3-month post-treatment were significantly lower in the control group than those in the experimental group (1-month: 3.74 ± 1.54 vs. 4.48 ± 1.46, p = .015; 3-month: 3.64 ± 2.21 vs. 5.40 ± 1.56, p < .001). At 3-month post-treatment, computed tomography (CT) scan revealed a significantly higher disease control rate in the experimental group than that in the control group (94.0% vs. 74.5%, p = .007). The median survival time in the experimental group was significantly longer than that in the control group (15-month vs. 9-month, p < .001). Conclusion The combination of coaxial percutaneous 125I seed implantation with arterial infusion chemotherapy could significantly alleviate abdominal pain, improve tumor control rates, and prolong survival time in patients with advanced PC.

Clinical efficacy and safety of erlotinib combined with chemotherapy in the treatment of advanced pancreatic cancer: A meta-analysis.

Advanced pancreatic cancer is resistant to chemotherapeutic drugs, resulting in limited treatment efficacy and poor prognosis. Combined administration of the chemotherapeutic gemcitabine and erlotinib is considered a potential first-line treatment for advanced pancreatic cancer. However, their comparative benefits and potential risks remain unclear. To assess the clinical efficacy and safety of erlotinib combined with other chemotherapy regimens for the treatment of advanced pancreatic cancer. Literature on the clinical efficacy and safety of erlotinib combined with chemotherapy for advanced pancreatic cancer was retrieved through an online search. The retrieved literature was subjected to a methodological qualitative assessment and was analyzed using the RevMan 5.3 software. Ten randomized controlled trials involving 2444 patients with advanced pancreatic cancer were included in the meta-analysis. Compared with chemotherapeutic treatment, erlotinib combined with chemotherapy significantly prolonged the progression-free survival time of pancreatic cancer patients [hazard ratio (HR) = 0.78, 95%CI: 0.66-0.92, P = 0.003]. Meanwhile, the overall survival (HR= 0.99, 95%CI: 0.72-1.37, and P = 0.95) and disease control rate (OR = 0.93, 95%CI: 0.45-0.91, P = 0.84) were not significantly favorable. In terms of safety, the erlotinib and chemotherapy combination was associated with a significantly higher risk of diarrhea (OR = 3.59, 95%CI: 1.63-7.90, P < 0.05) and rash (OR = 3.63, 95%CI: 1.64-8.01, P < 0.05) compared with single-agent chemotherapy. Moreover, the risk of vomiting (OR = 1.27, 95%CI: 0.62-2.59, P = 0.51), regurgitation/anorexia (OR = 1.61, 95%CI: 0.25-10.31, P = 0.62), and infection (OR = 0.72, 95%CI: 0.28-1.87, P = 0.50) were not significant in either group. Compared with a single chemotherapeutic modality, erlotinib combined with gemcitabine can prolong progression-free survival in pancreatic cancer, but does not improve survival benefit or disease control rate, and can increase the risk of diarrhea and rash.

Muscle and Adipose Wasting despite Disease Control: Unaddressed Side Effects of Palliative Chemotherapy for Pancreatic Cancer.

Muscle and adipose wasting during chemotherapy for advanced pancreatic cancer (aPC) are associated with poor outcomes. We aimed to quantify the contributions of chemotherapy regimen and tumour progression to muscle and adipose wasting and evaluate the prognostic value of each tissue loss. Of all patients treated for aPC from 2013-2019 in Alberta, Canada (n = 504), computed-tomography (CT)-defined muscle and adipose tissue index changes (∆SMI, ∆ATI, cm2/m2) were measured for patients with CT images available both prior to and 12 ± 4 weeks after chemotherapy initiation (n = 210). Contributions of regimen and tumour response to tissue change were assessed with multivariable linear regression. Survival impacts were assessed with multivariable Cox's proportional hazards models. Tissue changes varied widely (∆SMI: -17.8 to +7.3 cm2/m2, ∆ATI: -106.1 to +37.7 cm2/m2) over 116 (27) days. Tumour progression contributed to both muscle and adipose loss (-3.2 cm2/m2, p < 0.001; -12.4 cm2/m2, p = 0.001). FOLFIRINOX was associated with greater muscle loss (-1.6 cm2/m2, p = 0.013) and GEM/NAB with greater adipose loss (-11.2 cm2/m2, p = 0.002). The greatest muscle and adipose losses were independently associated with reduced survival (muscle: HR 1.72, p = 0.007; adipose: HR 1.73, p = 0.012; tertile 1 versus tertile 3). Muscle and adipose losses are adverse effects of chemotherapy and may require regimen-specific management strategies.

A retrospective real-world study of nimotuzumab combined with chemotherapy for advanced pancreatic cancer.

e16271 Background: Existing treatment options including gemcitabine-based therapy and 5FU-based chemotherapy have limited prognostic impact in advanced pancreatic cancer (APC): the median overall survival (mOS) was 6-11 months for 1st line therapy and 4-9 months for 2nd line therapy. Nimotuzumab (nimo), anti-EGFR monoclonal antibody, had been shown to be more effective against APC in two previous studies, PCS07 (a phase II study in Germany) and NOTABLE study (a phase III study in China). Although the NOTABLE study obtained an encouraging result in China, it focused on a narrow population, KRAS wild-type patients. This study aimed to explore the efficacy and safety of nimo in the real-world population with APC. Methods: In this retrospective observational study, patients with APC were treated with nimo and followed up in a real-world clinical setting. Demographic and clinical data of these patients were collected from electronic medical records of First Affiliated Hospital of Xi’an Jiaotong University from April 2018 to June 2022. The primary efficacy endpoint was overall survival. Results: A total of 104 patients (median age was 60.5 years, range 34-84) treated with nimo and chemotherapy were analyzed. Among them, 11 (10.6%) were in stage II (AJCC 8th edition), 23 (22.1%) were in stage III, and 70(67.3%) were in stage IV. The treatment regimen included gemcitabine plus nab-paclitaxel (AG, 80.77%), gemcitabine plus S-1 (GS, 10.58%) and others. The dosage of nimo was 200-400mg weekly, of which above 50% of patients received nimo 400 mg weekly. About 66 (63.5%) patients received nimo as 1st line therapy and 38 (36.5%) patients as 2nd line therapy. Up to July 5, 2022, the median follow-up time was 8.12 months and the mOS was not reached. The 1-year and 2-year OS rate were 80.2% and 74.4%, respectively. Further subgroup analysis showed that the mOS was also not reached in 1st line treatment of nimo (median follow-up time 8.77 months) as well as the 2nd line treatment of nimo (median follow-up time 7.62 months), showing a potential survival benefit. No grade 3 or above toxicities were observed. Conclusions: AG regimen was the most common therapy in clinical practice in China. The real world study displayed the addition of nimo would prolong the survival for APC, with a good safety profile.

Phase 2 study of weekly polymeric micelle-formulated paclitaxel plus gemcitabine in patients with recurrent and metastatic adenocarcinoma of the pancreas.

e16257 Background: Cremophor EL(CrEL), used to enhance drug solubility, may add paclitaxel’s toxicities such as hypersensitivity reactions or peripheral neuropathy. The rationale for developing an alternative paclitaxel formulation concerns CrEL-related side effects, and a novel paclitaxel delivery system might augment its therapeutic efficacy. GENEXOL-PM (GPM) is a novel polymeric micelle formulated paclitaxel free of CrEL. This is to report the efficacy and safety of the weekly combined chemotherapy with GPM and gemcitabine in patients with recurrent and metastatic adenocarcinoma of the pancreas conducted in multicenter, Republic of Korea. Methods: This was a multicenter, phase 2 study of weekly GENEXOL-PM plus gemcitabine in subjects with recurrent and metastatic adenocarcinoma of the pancreas. The patients who had met the inclusion/exclusion criteria were enrolled and received GPM (125 mg/m2) and gemcitabine (1000 mg/m2) intravenously on day 1, 8, and 15 in every 4 weeks, unless definite disease progression was confirmed. Tumor evaluation was conducted at the end of every 2 cycles according to Response Evaluation Criteria in Solid Tumors (RECIST). Pre-planned test and adverse reaction evaluation were managed after each cycle of drug administration and before the next cycle. The primary end point of this study was objective response rate, and the secondary end points were toxicity, progression free survival and overall survival. Results: Between January 2016 and February 2022, total 32 patients were enrolled; median age was 65 years; male (n=16) and female (n=16). 26 patients were assessable for efficacy. Overall response rate was 19.2% (5/26 patients) and clinical benefit rate (partial response + stable disease) was 34.6% (9/26 patients). The median progression-free survival and overall survival were 8 months, 22 months, respectively. The median number of cycles administered was 5.0 (range=1-21). Most common grade 3 or higher hematological toxicities were: neutropenia occurred in 9 patients (29.0%), neutrophil count decrease 5 patients (16.1%) and anemia 5 patients (16.1%). The most common grade 3/4 non-hematological toxicities were generalized muscle weakness 3 patients (11.5%), pneumonitis 3 patients (11.5%) and liver abscess 2 patients (4.3%). Conclusions: Treatment of advanced pancreatic cancer with combination of GENEXOL-PM and gemcitabine was generally well tolerated and showed a favorable toxicity profile. In this study, efficacy results of combination regimen were comparable to that observed historically with albumin-bound paclitaxel and gemcitabine combination. This regimen demonstrated chemotherapeutic effects to warrant further development when used as first-line chemotherapy for advanced pancreatic cancer. Future studies directly comparing GENEXOL-PM and albumin-bound paclitaxel are required. Clinical trial information: NCT02739633 .

Efficacy of the third-line chemotherapy in patients with advanced pancreatic cancer.

711 Background: First-line FOLFIRINOX or gemcitabine plus nab-paclitaxel (GNP) have improved the survival outcomes of patients with advanced pancreatic cancer (APC) and nano-liposomal irinotecan (nal-IRI) plus 5-FU/leucovorin is proven as the second-line agents. The current study aims to assess the efficacy of the third-line palliative chemotherapy in APC. Methods: Medical records were retrospectively reviewed in a single tertiary hospital between 2012 and 2020. The enrolled patients have APC who received the first and second-line chemotherapy. To fine the efficacy of the third-line chemotherapy, Kaplan Meier curve with cox-regression analysis was performed. Results: Of total 1,152 patients with pancreatic cancer, 362 patients were enrolled. Of these, 125 received the third-line chemotherapy and 238 received only supportive care after progression of the second-line chemotherapy. Median age at diagnosis was 60.3 years (range 36.0 – 86.0) and males were 52.0%. The first-line chemotherapy regimen was FOLFIRINOX (85, 68.0%), GNP (33, 26.4%), and others (7, 5.6%). The second-line chemotherapy regimen was GNP (55, 44.0%), FOLFIRINOX (34, 27.2%). As the third-line regimen, TS-1 and nal-IRI plus 5-FU/leucovorin were 73 (58.4%) and 20 (16.0%). The median overall survival (OS) from diagnosis was 18.0 months in all patients (95% CI, 14.6 – 21.4). The median OS after progression of the second-line therapy were 15.1 (95% CI, 12.8 – 17.5) and 8.5 weeks (95% CI, 7.7 – 9.4, p=0.007) between the patients with the third-line chemotherapy and supportive care only. Of the patients with the third-line chemotherapy, female showed the significant longer OS than male (12.4 (95% CI 10.2-14.6) vs. 6.6 weeks (95% CI 13.4-19.7), p=0.042). Conclusions: The current study suggested that proceeding with the third-line chemotherapy could be recommended in some patients. Females showed significantly more benefit than males. Further research on the selection for patient who will get the benefit from the third-line therapy is necessary.

Cutting edge of chemotherapy for advanced pancreatic cancer

Cutting edge of chemotherapy for advanced pancreatic cancer

Abstract PR006: Initial results of a cohort of advanced pancreatic cancer patients in a phase 1b Study of NGM120, a first-in-class anti-GDNF Family Receptor Alpha Like (GFRAL) antibody

Abstract Background: Elevated circulating growth differentiation factor 15 (GDF15) and increased GDF15 expression in tumor tissues has been observed in patients with advanced pancreatic cancer (APC). These changes were correlated with poor survival. Effects of GDF15 on tumor progression, metastasis and immune escape may play a role. NGM120, a novel antibody to GFRAL that blocks the effects of GDF15, has resulted both in antitumor and anti-cachexia effects in experimental models. Here we report updated findings of the ongoing Phase 1b study with NGM120 in patients with APC. Methods: Metastatic pancreatic cancer patients with elevated serum GDF15 were treated with NGM120 (30 or 100 mg, s.c., q4wks) in a 1st line setting in combination with Gem/nab-paclitaxel. Primary endpoints were safety and tolerability. Secondary endpoints were pharmacokinetics, preliminary evidence of antitumor activity (RECIST) and anti-cachexia effects. Results: Eight patients received NGM120 in combination with Gem/nab-paclitaxel. Median age was 67 years, all patients had advanced disease. NGM120 was well tolerated with no dose-limiting toxicities. Most of the AEs or SAEs observed were Gem/nab-paclitaxel related and none of them attributed to NGM 120 treatment. As of data cut off on March 25, 2022, preliminary results include 3 patients with PR (extending &amp;gt;32 wks), 3 patients SD; 2 patients discontinued early (before first post-dose scan) due to toxicity attributed to Gem/nab-paclitaxel. Among the 6 evaluable patients, the disease control rate (DCR) is 100%, mPFS has not been reached, 12-month survival rate (12-month OS) is 83.3%. Over the course of the study, 5/6 of the patients gained or maintained their body weight (BW) and 5/6 of the patients gained or maintained their lean body mass (LBM) based on maximum change from baseline. Conclusions: NGM120 given in combination with Gem/nab-paclitaxel to patients with APC resulted in a 50% ORR (3 PR in 6 evaluable patients), 100% DCR, 83.3% 12-month OS and a “not reached” mPFS. Compared to historical Gem/nab-paclitaxel data, these findings are encouraging and support the potential role of NGM120 in the treatment of patients with APC. The positive effects on BW and LBM is also encouraging compared to the historical cachexia rate of 30% observed within 12 weeks of starting first-line chemotherapy in APC. A sign of NGM120 engages the GDF15-GFRAL pathway in managing body weight regulation. A Ph2a study is ongoing to further evaluate NGM120 in combination with Gem/nab-paclitaxel in the 1st line setting for the treatment of APC. Citation Format: Andrew Hendifar, Efrat Dotan, Benjamin Weinberg, Edward Kim, Peter Hosein, Jian Luo, Jiping Zha, Alex DePaoli, Vladimir Hanes, Cecilia Tranmuchowski, Kefei Zhou, Carol Tseng, Hsiao Lieu. Initial results of a cohort of advanced pancreatic cancer patients in a phase 1b Study of NGM120, a first-in-class anti-GDNF Family Receptor Alpha Like (GFRAL) antibody [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr PR006.

98P Nanoliposomal irinotecan with fluorouracil and folinic acid, S-1 alone, or FOLFIRINOX as second-line chemotherapy for advanced pancreatic cancer after gemcitabine plus nab-paclitaxel: A pooled analysis of NAPOLEON-1 and NAPOLEON-2

Among nanoliposomal irinotecan plus fluorouracil and folinic acid (nal-IRI/5-FU/LV), S-1 alone (S-1), and FOLFIRINOX (FFX), the appropriate therapies for patients previously treated with gemcitabine plus nab-paclitaxel (GnP) for advanced pancreatic cancer (APC) are unclear.

Safety and efficacy analysis of PD-1 inhibitors in combination with chemotherapy for advanced pancreatic cancer.

Objective: To investigate the safety and efficacy of anti-PD-1 antibodies in combination with chemotherapy in the treatment of advanced pancreatic cancer. Methods: The clinical data of 18 patients with advanced pancreatic cancer who received anti-PD-1 antibody combined with chemotherapy were retrospectively analyzed. Safety, objective response rate, disease control rate, progression-free survivaland overall survival were analyzed. Results: One patient achieved a complete response, nine patients had a partial response,five patients had stable diseaseand three patients had progressive disease. Progression-free survivaland overall survivalwere shown to be significantly prolonged in both PD-L1-positive and high microsatellite instability (MSI-H) patients. Conclusion: Anti-PD-1 antibodies in combination with chemotherapy are safe and effective in the treatment of advanced pancreatic cancer.

Chemotherapy for advanced pancreatic cancer in older patients (literature review)

Elderly patients with malignant neoplasms of the pancreas are poorly represented in large clinical trials. Thus, in the MPACT and ACCORD study, the median age of patients with malignant neoplasms of the pancreas was 61 years, and it remains unclear whether the results obtained can be extrapolated to older patients, whom we most often encounter in real clinical practice. The vast majority of studies that analyzed the efficacy and tolerability of systemic chemotherapy in elderly and senile patients showed good tolerability of gemcitabine monotherapy, the tolerability of combined chemotherapy regimens among older patients with pancreatic adenocarcinoma varied between studies, but was expectedly higher than with monotherapy. with regard to survival rates, the effectiveness of systemic chemotherapy has also been shown here, especially combined regimens among elderly patients. But almost all studies were retrospective or included a small number of patients, which does not allow assessing the reliability of the results. The question of the advisability of intensifying chemotherapy in elderly and senile patients remains open.

P17-5 Early onset of anorexia-cachexia related worsening of cachexia symptoms during chemotherapy for pancreatic cancer

Anorexia-cachexia has been treatable by the ghrelin receptor agonist, anamorelin in pancreatic cancer. Few data on anorexia-cachexia make difficult to assess the efficacy of anamorelin. Framework of anorexia-cachexia includes incidence and timing of anorexia-cachexia, and its impact on weight loss, adverse event and survival during first-line chemotherapy for advanced pancreatic cancer.

Comparison of regional arterial chemotherapy and systemic intravenous chemotherapy for advanced pancreatic cancer: a systematic review and meta-analysis

Chemotherapy is the mainstay of treatment for advanced pancreatic cancer (stage III/IV). However, conventional systemic intravenous chemotherapy (SIC) has been unsatisfactory for pancreatic cancer. In recent years, regional arterial infusion chemotherapy (RAIC) has been clinically used as a new chemotherapy regimen for the treatment of advanced pancreatic cancer, but its efficacy is controversial. The purpose of this study was to evaluate the clinical efficacy and safety of RAIC. We searched literatures in databases such as PubMed, EMBASE, Cochrane Library, Web of Science, and CNKI. After screening, this meta-analysis finally included 9 randomized controlled trials (RCTs) with 444 patients (230 RAIC and 214 SIC). We used the Cochrane Risk of Bias 2.0 tool to assess risk of bias for included RCTs. Outcomes were overall survival (OS), overall response rate (ORR), adverse events rate (AER), and pain remission rate. Outcome indicators used relative risk (RR) and its 95% confidence interval (CI) as effect analysis statistics. The results showed that RAIC had some advantages over SIC in terms of ORR, OS, incidence of leukopenia, and pain remission. In conclusion, compared with SIC, RAIC has better clinical efficacy and lower toxicity in the treatment of advanced pancreatic cancer.

Efficacy and safety of FOLFIRINOX as second-line chemotherapy for advanced pancreatic cancer after gemcitabine-based therapy: A systematic review and meta-analysis.

ObjectiveTo undertake a meta-analysis of the treatment effects of different second-line chemotherapy regimens compared with FOLFIRINOX (FOL [folinic acid], F [fluorouracil], IRIN [irinotecan], OX [oxaliplatin]) after failure of gemcitabine-based first-line therapy in patients with pancreatic cancer.MethodsThis meta-analysis searched electronic databases, including Embase®, Medline, PubMed® and the Cochrane library, for eligible studies that reported the use of FOLFIRINOX and other drug regimens as second-line chemotherapy after failure of gemcitabine-based chemotherapy. Pooled analyses for progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR) and grade 3/4 treatment-emergent adverse events (TRAEs) were undertaken.ResultsThe analysis included six studies with a total of 858 patients. Compared with the three other second-line regimens, FOLFIRINOX had a significantly longer PFS (hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.52, 0.89) and OS (HR 0.71, 95% CI 0.59, 0.86); and a significantly better ORR (HR 0.43, 95% CI 0.23, 0.80) and DCR (HR 0.71, 95% CI 0.58, 0.88). However, grade 3/4 adverse events were more frequently reported in patients administered FOLFIRINOX compared with the other three regimens.ConclusionFOLFIRINOX is recommended as a second-line chemotherapy regimen for patients with pancreatic cancer that have failed on gemcitabine-based first-line therapy.Research Registry number: reviewregistry1300

Biomarker-oriented study of pembrolizumab in combination with chemotherapy in chemotherapy-naïve advanced pancreatic cancer: A phase 2 trial-in-progress.

TPS639 Background: Pancreatic cancer (PC) is well-known as a strongly immunosuppressive tumor. The tumor microenvironment of PC play a fundamental part in maintaining a non-immunogenic and immuno-suppressive environment through the production of inhibitory cytokines and complex interaction between tumor cells, regulatory T cells, and myeloid-derived suppressor cells (Li KY et al. 2020). However, through integrated genomics and immunophenotyping, the immune-rich type had a relatively good prognosis in advanced PC (Wartenberg M et al. 2018). Based on this, various attempts have been made to apply immune checkpoint inhibitor (ICI) to PC. Disappointingly, ICI monotherapy is ineffective in most advanced PCs, and a strategy of combining ICI with ICI, chemotherapy or targeted therapy has been recently tried. However, the mechanism of immune modulation induced by ICI in combination with chemotherapy in PC is still not well-known, so biomarker studies are needed to understand the role of immunotherapy in advanced PC. Also based on this, it is expected to develop an effective ICI treatment strategy in PC. This study is a non-randomized, parallel assignment phase 2 trial aimed to explore dynamic modulation of the immune system caused by co-administration of pembrolizumab and cytotoxic chemotherapy in patients with advanced PC. Methods: Eligible patients have recurred or metastatic pancreatic cancer. Patients who have received chemotherapy for advanced PC are excluded, except for previous adjuvant chemotherapy. Patients who have received ICI are excluded. There are 2 chemotherapy cohorts (FOLFIRINOX, n=41; Gemcitabine/Nab-paclitaxel, n=36). Patients enrolled in the FOLFIRINOX cohort will receive pembrolizumab 200mg intravenously once every 3 weeks, plus FOLFIRINOX chemotherapy every 2 weeks. In Gemcitabine/Nab-paclitaxel cohort, patients will receive gemcitabine 1000mg/m2 plus nab-paclitaxel 125mg/m2 day 1, 8, 15 of a 4-week cycle, plus pembrolizumab 200mg intravenously once every 3 weeks. The primary endpoint is objective response rate, with key secondary endpoints including progression-free survival, duration of response, disease control rate, overall survival, safety, and patient-reported outcome. For evaluating metabolic response, 18F-FDG PET-CT scan will be conducted before treatment and at the first response evaluation. Tumor tissue biopsies are performed three times in total: screening, the first response evaluation, and disease progression. Blood samples are being collected every cycles for translational biomarker studies. Clinical trial information: NCT04447092.

Intra-Arterial Infusion Chemotherapy in Advanced Pancreatic Cancer: A Comprehensive Review.

Simple SummaryPancreatic cancer has a very poor prognosis. The few available therapeutic options are characterized by low efficacy and high toxicity due to the intrinsic chemoresistance of this tumor type. To improve clinical results, some clinical trials have evaluated regional chemotherapy as a treatment option for PC. The pancreatic arterial infusion of chemotherapeutics has the aim of obtaining higher local concentrations of drugs and, at the same time, of limiting systemic toxicity. This therapeutic approach has already been successfully evaluated for the treatment of several types of tumors. Regarding advanced pancreatic cancers, only a few clinical studies have investigated the safety and efficacy of this treatment, with very promising results. Therefore, in this review, we summarize literature data on the clinical approaches to pancreatic arterial drug administration for the treatment of advanced PC to deepen knowledge on this topic.Advanced pancreatic cancer (PC) has a very poor prognosis due to its chemoresistant nature. Nowadays, only a few therapeutic options are available for PC, and the most effective ones are characterized by low response rates (RRs), short progression-free survival and overall survival, and severe toxicity. To improve clinical results, small series studies have evaluated loco-regional chemotherapy as a treatment option for PC, demonstrating its dose-dependent sensitivity towards the tumor. In fact, pancreatic arterial infusion (PAI) chemotherapy allows higher local concentrations of chemotherapeutic agents, sparing healthy tissues with a lower rate of adverse events compared to systemic chemotherapy. This therapeutic approach has already been evaluated in different types of tumors, especially in primary and metastatic liver cancers, with favourable results. With regard to advanced PC, a few clinical studies have investigated the safety and efficacy of PAI with promising results, especially in terms of RRs compared to systemic chemotherapy. However, clear evidence about its efficacy has not been established yet nor have the underlying mechanisms leading to its success. In this review, we aim to summarize the literature data on the clinical approaches to pancreatic arterial drug administration in terms of techniques, drug pharmacokinetics, and clinical outcomes for advanced PC.

Gene Therapy Using Nanocarriers for Pancreatic Ductal Adenocarcinoma: Applications and Challenges in Cancer Therapeutics.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide, and its incidence is increasing. PDAC often shows resistance to several therapeutic modalities and a higher recurrence rate after surgical treatment in the early localized stage. Combination chemotherapy in advanced pancreatic cancer has minimal impact on overall survival. RNA interference (RNAi) is a promising tool for regulating target genes to achieve sequence-specific gene silencing. Here, we summarize RNAi-based therapeutics using nanomedicine-based delivery systems that are currently being tested in clinical trials and are being developed for the treatment of PDAC. Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) genome editing has been widely used for the development of cancer models as a genetic screening tool for the identification and validation of therapeutic targets, as well as for potential cancer therapeutics. This review discusses current advances in CRISPR/Cas9 technology and its application to PDAC research. Continued progress in understanding the PDAC tumor microenvironment and nanomedicine-based gene therapy will improve the clinical outcomes of patients with PDAC.

The clinical outcomes of second-line chemotherapy in patients with advanced pancreatic cancer: a retrospective study.

BackgroundDespite recent advances in first-line chemotherapy for advanced pancreatic cancer, standard treatment after the failure of initial chemotherapy has not been established. Hence, we aimed to retrospectively analyze the clinical characteristics and outcomes of second-line chemotherapy in patients with advanced pancreatic cancer. MethodsWe reviewed the clinical data of patients with advanced pancreatic cancer who underwent palliative chemotherapy at Kosin University Gospel Hospital between January 2013 and October 2020.ResultsAmong 366 patients with advanced pancreatic cancer who had received palliative chemotherapy, 104 (28.4%) underwent at least one cycle of second-line chemotherapy. The median age of the patients at the time of initiating second-line treatment was 62 years (interquartile range, 57–62 years), and 58.7% (61 patients) of them were male. The common second-line chemotherapy regimens were 5-fluorouracil (FU) plus leucovorin, irinotecan, and oxaliplatin (33 patients, 31.7%); gemcitabine/nab-paclitaxel (29, 27.9%), gemcitabine±erlotinib (13, 12.5%); and oxaliplatin and 5-FU/leucovorin (12, 11.5%). The median overall survival (OS) and progression-free survival were 6.4 months (95% confidence interval [CI], 4.5–8.6 months) and 4.5 months (95% CI, 2.7–6.3 months), respectively. In a multivariate analysis, poor performance status (PS) (hazard ratio [HR], 2.247; p=0.021), metastatic disease (HR, 2.745; p=0.011), and elevated carcinoembryonic antigen (CEA) levels (HR, 1.939; p=0.030) at the beginning of second-line chemotherapy were associated with poor OS.ConclusionThe survival outcome of second-line chemotherapy for advanced pancreatic cancer remains poor. However, PS, disease extent (locally advanced or metastatic), and CEA level may help determine patients who could benefit from second-line treatment.

Real-world evidence on first- and second-line palliative chemotherapy in advanced pancreatic cancer.

In spite of recent diagnostic and therapeutic advances, the prognosis of pancreatic ductal adenocarcinoma (PDAC) remains very poor. As most patients are not amenable to curative intent treatments, optimized palliative management is highly needed. One key question is to what extent promising results produced by randomized controlled trials (RCTs) correspond to clinically meaningful outcomes in patients treated outside the strict frames of a clinical trial. To answer such questions, real-world evidence is necessary. The present paper reviews and discusses the current literature on first- and second-line palliative chemotherapy in PDAC. Notably, a growing number of studies report that the outcomes of the two predominant first-line multidrug regimens, i.e. gemcitabine plus nab-paclitaxel (GnP) and folfirinox (FFX), is similar in RCTs and real-life populations. Outcomes of second-line therapy following failure of first-line regimens are still dismal, and considerable uncertainty of the optimal management remains. Additional RCTs and real-world evidence studies focusing on the optimal treatment sequence, such as FFX followed by GnP or vice versa, are urgently needed. Finally, the review highlights the need for prognostic and predictive biomarkers to inform clinical decision making and enable personalized management in advanced PDAC.