Articoli di riviste: "Gem therapy"

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Fukahori, Masaru. "Efficacy of gemcitabine as second-line therapy after S-1 therapy failure in advanced pancreatic carcinoma." Journal of Clinical Oncology 30, n. 4_suppl (1 febbraio 2012): 248. http://dx.doi.org/10.1200/jco.2012.30.4_suppl.248.

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248 Background: Gemcitabine (GEM) and GEM-containing combination chemotherapy have been established as standard first-line therapies for advanced pancreatic carcinoma (APC). In the GEST study, a phase III clinical trial that compared the results for GEM, S-1, and GEM+S-1 therapies, there was no significant difference between overall survival (OS) for GEM and GEM+S-1; S-1 and GEM had similar efficacies as first-line treatment for APC. Therefore, S-1 is expected to be used as first-line therapy. In our study, we have evaluated the efficacy and outcomes of second-line GEM therapy after S-1 therapy failure in APC. Methods: We retrospectively examined the data for 27 patients (pts) with APC refractory to first-line S-1 therapy. All the pts had undergone second-line GEM therapy during October 2000–February 2009 at National Cancer Center Hospital after first-line S-1 therapy. Tumor responses were analyzed using Response Evaluation Criteria in Solid Tumors. The Kaplan-Meier method was used to evaluate tumor progression and survival. Results: The Eastern Cooperative Oncology Group Performance Status was 0 or 1. The male:female ratio was 16:11 and median age was 62 years (range, 42–75 years). Four pts (14%) exhibited a partial response to second-line GEM therapy, 11 (40%) showed stable disease, and 12 (44%) showed progressive disease. Grade 3 adverse events for second-line GEM therapy were neutropenia in 2 pts and upper gastrointestinal hemorrhage in 1 pt. Grade 4 adverse events were not observed. The median progression-free survival was 77 days (95% confidence interval, 33–121 days) and the median OS after second-line GEM therapy was 240 days (95% confidence interval, 156–324 days). Conclusions: Although this study had a small sample population and retrospective design, the results indicate that GEM has good antitumor activity with tolerable toxicity. Second-line GEM therapy was found to be effective after first-line S-1 therapy failure in APC.

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Chiorean, E. Gabriela, Daniel D. Von Hoff, Josep Tabernero, Robert El-Maraghi, Wen Wee Ma, Michele Reni, Marion Harris et al. "Second-line therapy after nab-paclitaxel plus gemcitabine or after gemcitabine for patients with metastatic pancreatic cancer". British Journal of Cancer 115, n. 2 (28 giugno 2016): 188–94. http://dx.doi.org/10.1038/bjc.2016.185.

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Abstract Background: This exploratory analysis evaluated second-line (2L) therapy for metastatic pancreatic cancer in a large phase 3 trial (MPACT). Methods: Patients who received first-line (1L) nab-paclitaxel+gemcitabine (nab-P+Gem) or Gem were assessed for survival based on 2L treatment received. Multivariate analyses tested influence of treatment effect and prognostic factors on survival. Results: The majority of 2L treatments (267 out of 347, 77%) contained a fluoropyrimidine (5-fluorouracil or capecitabine). Median total survival (1L randomisation to death) for patients who received 2L treatment after 1L nab-P+Gem vs Gem alone was 12.8 vs 9.9 months (P=0.015). Median total survival for patients with a fluoropyrimidine-containing 2L therapy after nab-P+Gem vs Gem was 13.5 vs 9.5 months (P=0.012). Median 2L survival (duration from start of 2L therapy to death) was 5.3 vs 4.5 months for nab-P+Gem vs Gem, respectively (P=0.886). Factors significantly associated with longer post-1L survival by multivariate analyses included 1L nab-P+Gem, receiving 2L treatment, longer 1L progression-free survival, and Karnofsky performance status⩾70 and neutrophil-to-lymphocyte ratio⩽5 at the end of 1L treatment. Conclusions: These findings support the use of 2L therapy for patients with metastatic pancreatic cancer. Fluoropyrimidine-containing treatment after 1L nab-P+Gem is an active regimen with significant clinical effect.

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Esim, Ozgur, Cansel K. Ozkan, Meral Sarper, Ayhan Savaser e Yalcin Ozkan. "Development of Gemcitabine Loaded PLGA/Lecithin Nanoparticles for Non-Small Cell Lung Cancer Therapy". Current Drug Delivery 17, n. 7 (15 settembre 2020): 622–28. http://dx.doi.org/10.2174/1567201817666200512094145.

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Background: Compared to polymeric nanoparticles prepared using non-lipid surfactants, lecithin addition forms larger nanoparticles and exhibits higher drug loading and the stability of nanoparticles can be conferred by adding Vitamin E Polyethylene Glycol Succinate (TPGS) into the formulation. Aim: The aim of this study is to prepare Gemcitabine (Gem) loaded lecithin/PLGA nanoparticles. Moreover, the effect of TPGS and sodium cholate (SK) on the preparation of lecithin/PLGA nanoparticles was compared. Methods: It was found that while PC addition into PLGATPGS nanoparticles formed larger particles (251.3± 6.0 nm for Gem-PLGATPGS NPs and 516,9 ± 3.9 nm for Gem-PLGA-PCTPGS NPs), the particle size of PLGASK nanoparticles was not affected by lecithin addition (p>0.05). Results: In cytotoxicity studies, it was found that the SK-MES-1 cell inhibition rates of Gem-PLGATPGS NPs, Gem-PLGA-PCTPGS NPs, Gem-PLGASK NPs, Gem-PLGA-PCSK NPs were similar with free Gem (p>0.05). In cytotoxicity studies, it was found that the encapsulation into nanoparticles did not change the cytotoxicity of the drug. However, higher cellular uptake has been observed when the lecithin was used in the preparation of PLGA nanoparticles. Conclusion: Compared with free Gem, the Gem-loaded nanoparticles enhanced the uptake of the drug by SK-MES-1 cells which can increase the effect of gemcitabine for non-small cell lung cancer therapy.

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Kasahara, K., T. Kita, K. Shibata, K. Nishi, Y. Ishiura, T. Araya, Y. Tambo, A. Sakai, H. Kimura e M. Fujimura. "A phase II study of gemcitabine and vinorelbine combination followed by sequential gefitinib monotherapy in elderly patients with non-small cell lung cancer". Journal of Clinical Oncology 27, n. 15_suppl (20 maggio 2009): e19040-e19040. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e19040.

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e19040 Background: Gemcitabine (GEM) and vinorelbine (VNR) combination have demonstrated activity as a 1st-line treatment in elderly patients with advanced non-small-cell lung cancer (NSCLC). Gefitinib (GEF) is effective as a 2nd-line treatment for NSCLC. We conducted a multicenter phase II trial to evaluate the efficacy and toxicity for treatment of GEM+VNR followed by sequential GEF in elderly patients (pts) with advanced or metastatic NSCLC. Primary endpoint is response rate, secondary endpoints were safety, progression-free survival (PFS), and overall survival (OS). Methods: Eligibility required hitologically or cytologically comfirmed NSCLC, no prior therapy, measurable lesion(s), ECOG PS 0–2, age equal to or over 70 years, and adequate organ functions. Patients were received 3 cycles, each at 4-week intervals, of GEM (1000 mg/m2, d 1, 15) and VNR (25mg/m2 d 1, 15), followed by 250 mg of GEF daily until disease progression or unacceptable toxicity. Results: Between June 2004 and November 2007, 60 pts were enrolled and 2 pts withdrew consent. Fifty-eight pts (35 male and 23 female, median age 77 years) were evaluated. Median number of GEM+VNR administrations was 3 (range 1–3). Median duration of GEF was 101 days (range 9–652 days). Grade 3/4 toxicities included leucopenia (29%), neutoropenia (40%), anemia (12%), febrile neutropenia (9%), and anorexia (9%) during GEM+VNR, anorexia (2%), and constipation (2%) during GEF. Best response rate of GEM+VNR was 17% and that after sequential GEF was 31%. Median PFS and median OS were 4.2 months and 12.6 months, respectively. Response rate, PFS, and OS were significantly favorable in female and never-smoker. Conclusions: Sequential treatment consisted with GEM+VNR and GEF was feasible with acceptable toxicities in elderly patients with NSCLC. [Table: see text]

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Korniichuk, N. M., S. P. Turanska, A. L. Petranovska, M. V. Abramov, P. P. Gorbyk, N. Yu Luk'yanova, N. V. Kusyak e V. F. Chekhun. "Magnetically sensitive nanocomposites for targeted antitumor therapy with application of gemcitabine". Himia, Fizika ta Tehnologia Poverhni 11, n. 4 (30 dicembre 2020): 528–38. http://dx.doi.org/10.15407/hftp11.04.528.

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The aim of the work is synthesis and study on the properties of polyfunctional magnetosensitive nanocomposites (NC) and target-directed magnetic fluids (MF) based on physiological solution (PS), magnetite, gemcitabine (GEM) and HER2 antibodies (AB), promising for use in targeted antitumor therapy against MDA-MB-231 aggressive tumor cells of triple-negative human breast cancer (BC) with high proliferative and metastatic activity. The specific surface area (Ssp) of samples was determined by the method of thermal desorption of nitrogen using a device KELVIN 1042 of “COSTECH Instruments”. The size of nanoparticles (NP) has been estimated by the formula DBET = 6/(ρSBET), where ρ is the density of NC particle, SBET is the value of the specific surface area calculated by the polymolecular adsorption theory of Brunauer, Emmett and Teller (BET). The surface condition of nanodispersed samples was studied by IR spectroscopy (“Perkin Elmer” Fourier spectrometer, a model 1720X). To calculate the concentration of hydroxyl groups on the surface of nanostructures, the method of differential thermal analysis was used in combination with differential thermogravimetric analysis. The thermograms were recorded using a derivatograph Q-1500D of MOM firm (Hungary) in the temperature range of 20–1000 °C at a heating rate of 10 deg/min. X-ray phase analysis of nanostructures was performed using a diffractometer DRON-4-07 (CuKα radiation with a nickel filter in a reflected beam, the Bragg-Brentano focusing). The size and shape of NP were determined by electron microscopy (a transmission electron microscope (TEM) JEM-2100F (Japan)). The hysteresis loops of the magnetic moment of the samples were measured using a laboratory vibration magnetometer of Foner type at room temperature. Measurement of optical density, absorption spectra and GEM concentration in solutions was performed by spectrophotometric analysis (Spectrometer Lambda 35 UV/Vis Perkin Elmer Instruments). The amount of adsorbed substance on the surface of magnetite was determined using a spectrophotometer at λ = 268 nm from a calibration graph. The thickness of the adsorbed layer of GEM in the composition of Fe3O4@GEM NC was determined by magnetic granulometry. To study the direct cytotoxic/cytostatic effect of a series of experimental samples of MF based on PS, Fe3O4 NP, GEM, HER2 AB, as well as MF components in mono- or complex use, onto MDA-MB-231 cells in vitro, IC50 index was determined. MF were synthesized on the basis of single-domain Fe3O4 and PS, stabilized with sodium oleate (Ol.Na) and polyethylene glycol (PEG), containing GEM and HER2 (Fe3O4@GEM/Ol.Na/PEG/HER2+PS). The cytotoxic/cytostatic activity of MF against MDA-MB-231 cells was studied. It was found that as a result of application of synthesized MF composed of Fe3O4@GEM/Ol.Na/PEG/HER2+PS at the concentration of magnetite of 0.05 mg/mL, GEM - 0.004 mg/mL and HER2 AB - 0.013 μg/mL, a synergistic effect arose, with reduction of the amount of viable BC cells to 51 %. It has been proved that when using MF based on targeted Fe3O4/GEM/HER2 complex, the increased antitumor efficacy is observed compared to traditional use of the drug GEM, with a significant reduction (by four times) of its dose. The high cytotoxic/cytostatic activity of Fe3O4/GEM/HER2 complexes is explained by the fact that endogenous iron metabolism disorders play a significant role in the mechanisms of realization of the apoptotic program under the influence of nanocomposite. Thus, when the nanocomposite system contains Fe3O4/GEM/HER2 complexes in MDA-MB-231 cells, a significant increase is observed in the level of “free iron”, which favours formation of reactive oxygen species and causes oxidative stress (Fenton reaction). The consequences of oxidative stress are induction of apoptosis, enhancement of lipid peroxidation processes, as well as structural and functional rearrangement of biological membranes. The prospects have been shown of further studies of Fe3O4@GEM/Ol.Na/PEG/HER2+PS MF in order to create on their basis a magnetically carried remedy for use in targeted antitumor therapy.

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Chen, Li-Tzong, Andrea Wang-Gillam, Shan Yanshen, Teresa Macarulla, Jean-Frédéric Blanc, Richard Hubner, Chang-Fang Chiu et al. "Efficacy and safety of liposomal irinotecan (nal-IRI) + 5-fluorouracil and leucovorin (5-FU/LV) in patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC) who previously received gemcitabine (gem)-based therapy: Post-hoc analysis of the NAPOLI-1 trial." Journal of Clinical Oncology 35, n. 4_suppl (1 febbraio 2017): 303. http://dx.doi.org/10.1200/jco.2017.35.4_suppl.303.

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303 Background: nal-IRI+5-FU/LV is approved in the United States and Taiwan for pts with mPDAC previously treated with gem-based therapy based on the NAPOLI-1 study which showed that nal-IRI+5-FU/LV improved overall survival (OS) vs 5-FU/LV (6.1 vs 4.2 mo; HR, 0.67; 95% CI, 0.49-0.92; P = 0.012; Wang-Gillam et al, Lancet. 2016). This post hoc analysis evaluated the efficacy and safety of nal-IRI+5-FU/LV in subgroups of pts defined by prior gem regimen including gem monotherapy and gem combinations (combo). Methods: This analysis (data cutoff, Nov 2015) focuses on the 236 pts assigned to nal-IRI+5-FU/LV q2w (n = 117) or 5-FU/LV qw for weeks 1-4 q6w cycle (n = 119). Pts previously received gem-based therapy in a neoadjuvant, adjuvant, locally advanced, or metastatic setting. Results: Of 117 pts in the nal-IRI+5-FU/LV arm, 53 (45%) previously received gem monotherapy and 64 (55%) previously received gem combo including erlotinib (n = 9) or nab-paclitaxel (n = 20). Of the 119 pts in the 5-FU/LV arm, 55 (46%) previously received gem monotherapy and 64 (54%) previously received gem combo including erlotinib (n = 17) or nab-paclitaxel (n = 11). Nal-IRI+5-FU/LV improved median OS, median PFS, and ORR vs 5-FU/LV, regardless of prior therapy (Table). Grade ≥3 treatment-emergent adverse events were not influenced by prior treatment. Clinical trial information: NCT01494506. Conclusions: These resultsshow consistent benefit of nal-IRI+5-FU/LV treatment across subgroups of pts who previously received gem therapy and support the ASCO guidelines recommending nal-IRI+5-FU/LV for this pt population. These analyses may be limited by the small sample size of treatment arms.[Table: see text]

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Xin, Xiaofei, Virender Kumar, Feng Lin, Vinod Kumar, Rajan Bhattarai, Vijaya R. Bhatt, Chalet Tan e Ram I. Mahato. "Redox-responsive nanoplatform for codelivery of miR-519c and gemcitabine for pancreatic cancer therapy". Science Advances 6, n. 46 (novembre 2020): eabd6764. http://dx.doi.org/10.1126/sciadv.abd6764.

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Desmoplastic and hypoxic pancreatic cancer microenvironment induces aberrant expression of miRNAs and hypoxia-inducible factor-1α (HIF-1α) responsible for gemcitabine (GEM) resistance. We demonstrated that miR-519c was down-regulated in pancreatic cancer and transfection of miR-519c in GEM-resistant pancreatic cancer cells inhibited HIF-1α level under hypoxia. We synthesized redox-sensitive mPEG-co-P(Asp)-g-DC-g-S-S-GEM polymer, with GEM payload of 14% (w/w) and 90% GEM release upon incubation with l-glutathione. We synthesized mPEG-co-P(Asp)-g-TEPA-g-DC for complex formation with miRNA. Chemical modification of miR-519c with 2′-O-methyl phosphorothioate (OMe-PS) at 3′ end enhanced its stability and activity without being immunogenic. Epidermal growth factor receptor targeting peptide GE11 decoration increased tumor accumulation of micelles after systemic administration and significantly inhibited orthotopic desmoplastic pancreatic cancer growth in NSG mice by down-regulating HIF-1α and genes responsible for glucose uptake and cancer cell metabolism. Our multifunctional nanomedicine of GEM and OMe-PS–miR-519c offers a novel therapeutic strategy to treat desmoplasia and hypoxia-induced chemoresistance in pancreatic cancer.

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Muniz Kovtun, Jeanette, Konstantin Kovtun, Koenraad Mortele, James Moser e Andrea J. Bullock. "Neoadjuvant therapy outcomes in nonmetastatic pancreatic cancer." Journal of Clinical Oncology 36, n. 4_suppl (1 febbraio 2018): 501. http://dx.doi.org/10.1200/jco.2018.36.4_suppl.501.

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501 Background: The optimal multidisciplinary treatment algorithm for pancreatic ductal adenocarcinoma (PDAC) is not well established. We studied outcomes in non-metastatic PDAC treated with chemotherapy and stereotactic body radiation therapy (SBRT) with or without pancreatic resection. Methods: Between August 2011 and July 2015, 73 patients with non-metastatic PDAC were treated with chemotherapy and SBRT with or without resection. Variables considered included: ECOG, CA 19-9, clinical stage, vascular involvement, pathologic stage and margin status. Resectability status was determined by an expert abdominal radiologist on initial staging imaging. Chemotherapy included FOLFIRINOX, FOLFOX, gemcitabine monotherapy (gem) or with nab-paclitaxel (gem/nab). SBRT was delivered as 30 Gy in 3 fractions over 5 days via CyberKnife. The Kaplan-Meier method and log-rank test were used to compare median overall survival (mOS), local progression free survival (LPFS) and metastasis free survival (MFS). Results: After a median follow-up of 19.3 months (mo) the mOS was 30.0 mo (95% CI, 19.4 to 36.5). The surgical group had longer mOS (36.5 vs 19.4 mo; P < 0.001), LPFS (29.0 vs 16.3 mo; P = 0.03) and MFS (29.0 vs 15.1 mo; P < 0.001) as compared to the nonsurgical group. FOLFIRINOX or gem/nab was associated with better mOS as compared to other chemotherapy (33.2 vs 12.8 mo; P < 0.001). There was a trend towards longer mOS in pts with initial imaging deemed less resectable (36.5 vs 30.1 vs 13.0 mo in unresectable vs borderline vs resectable; P = 0.19). In a multivariate analysis significant predictors of OS were resection, ECOG and FOLFIRINOX or gem/nab chemotherapy. Conclusions: Patients who had surgery after neoadjuvant chemotherapy and SBRT had significantly longer mOS, LPFS and MFS than those without surgery. FOLFIRINOX or gem/nab and better ECOG were also associated with improved outcomes. Worse resectablity status per imaging was associated with longer OS despite less likelihood of surgery; This may reflect more intensive neoadjuvant therapy or suggest that radiologic resectability status is a poor predictor of OS. Further investigation of factors underlying this discrepancy may have implications on neoadjuvant strategy and resectability determination.

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Awasthi, Niranjan, Margaret A. Schwarz e Roderich Schwarz. "Adding targeted inhibition of PI3K and MAPK signaling pathways to standard chemotherapy in experimental pancreatic cancer." Journal of Clinical Oncology 34, n. 4_suppl (1 febbraio 2016): 278. http://dx.doi.org/10.1200/jco.2016.34.4_suppl.278.

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278 Background: Treatment of pancreatic ductal adenocarcinoma (PDAC) remains a formidable challenge as gemcitabine (Gem) plus nab-paclitaxel (NPT) represent the current standard for systemic therapy of advanced PDAC. More than 90% of PDAC tumors harbor an activating mutation in the KRAS oncogene. Currently no therapeutics exist that can effectively target this oncogene product, but alternative strategies focus on inhibition of downstream effectors of KRAS signaling pathways. The RAF-MEK-ERK (MAPK) and the AKT-PI3K signaling pathways are well-described mediators of KRAS induced transformation and tumorigenesis and can be explored as targets for combination therapy. Methods: We evaluated combination treatment benefits of NPT+Gem with the MEK inhibitor trametinib (Tra) and the AKT inhibitor MK-2206 (MK) in experimental xenografts to test their therapeutic potential against PDAC. Results: Median animal survival in human intraperitoneal PDAC xenografts in mice revealed that the median survival was 21 days in controls; this was significantly improved by the NPT+Gem combination (35 days, a 67% increase over controls, p = 0.0007). Median survival was further increased by addition of MK-2206 or trametinib to NPT+Gem chemotherapy group: NPT+Gem+MK (39 days, a 86% increase over controls, p = 0.0003), NPT+Gem+Tra (43 days, a 105% increase over controls, p = 0.0003) and NPT+Gem+MK+Tra (48 days, a 129% increase over controls, p = 0.002). In human subcutaneous PDAC xenografts, MK-2206 or trametinib were able to enhance NPT+Gem effects. Compared to controls (100±34.8), the percent net local tumor growth in different therapy groups was: NPT+Gem 21.8±5.9 (p = 0.003), NPT+Gem+MK 17.2±4.8 (p = 0.002), NPT+Gem+Tra 7.1±11.2 (p = 0.002) and NPT+Gem+MK+Tra 5.7±9.1 (p = 0.001). In vivo effects of Tra and MK correlated with reduced expression of phospho-ERK and phospho-AKT in Western blots of tumor samples. Conclusions: These findings suggest that the effects of NPT+Gem can be enhanced through combined inhibition of MAPK and PI3K signaling pathways, which clinically could yield in improved antitumor results.

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Wang, Jian, Jiasui Chai, Lei Liu, Zilin Cui, Dongming Duan, Rui Shi e Yamin Zhang. "Dual-functional melanin-based nanoliposomes for combined chemotherapy and photothermal therapy of pancreatic cancer". RSC Advances 9, n. 6 (2019): 3012–19. http://dx.doi.org/10.1039/c8ra09420a.

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GEM-Mel-Lip converted light to heat based on melanin after entering the tumor cells, and then the phospholipid fluidity was increased under the hyperthermia generated, resulting in the release of GEM.

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Cockrum, Paul, Andy Surinach, Stella Arndorfer, Jim M. Koeller e George P. Kim. "National Comprehensive Cancer Network (NCCN) category I/FDA-approved metastatic pancreatic adenocarcinoma (mPDAC) treatments in commercially insured patients: An analysis of inpatient (IP) and emergency room (ER) admissions." Journal of Clinical Oncology 38, n. 15_suppl (20 maggio 2020): e16739-e16739. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e16739.

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e16739 Background: There are currently four NCCN category 1 systemic regimens approved in the United States for the treatment of mPDAC: FOLFIRINOX (FFX), gemcitabine+nab-paclitaxel (gem+nab-P), gemcitabine monotherapy (gem), and liposomal irinotecan + 5-fluorouracil/leucovorin (5-FU/LV) following progression with gem-based therapy. There is limited real-world research on the IP admissions and ER visit healthcare resource utilization (HRU) of patients receiving these treatments. Methods: Using the IQVIA PharMetrics Plus administrative claims database, data were analyzed for adult patients with mPDAC treated with NCCN category 1 regimens in first through fourth line of therapy between January 1, 2014 and May 31, 2019. For each line of therapy, continuous treatment was defined as the time from first administration of a therapy until the last administration. Mean all-cause and mPDAC-related IP admissions, ER visits, inpatient length of stay (LOS) during treatment were assessed. Results: Of the 2,731 patients with mPDAC included in the study, 101 (3.7%) were treated with a liposomal irinotecan based regimen, 1,316 (48.2%) were treated with gem+nab-P, 612 (22.4%) with FFX, and 624 (22.8%) with gem in any treatment line. The mean number of IP admissions was 1.2 for liposomal irinotecan treated patients, 1.5 for gem+nab-P, 1.5 for FFX, and 1.2 for gem. Among patients with at least one IP admission the mean LOS was 4.5 days for liposomal irinotecan, 5.4 days for gem+nab-P, 3.8 for FFX, and 5.1 for gem treated patients. Patients treated with liposomal irinotecan had a mean of 1.3 ER visits during treatment. Gem+nab-P, FFX, and gem-treated patients experienced 1.7, 1.4, and 1.8 mean ER visits, respectively. Mean mPDAC-related IP admissions ranged from 1.1 – 1.5, ER visits ranged from 1.1 – 1.7, and mean LOS ranged from 3.8 – 5.5 days. Conclusions: In this descriptive retrospective study patients receiving liposomal irinotecan, across all treatment episodes, generally experienced numerically lower mean IP admissions and ER visits. LOS was similar across all regimens. Further studies are necessary to characterize the IP and ER HRU burden among mPDAC patients treated with approved regimens.

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Philip, Philip Agop, Jill Lacy, Scot D. Dowden, Javier Sastre, Venu Gopal Bathini, Dana Backlund Cardin, Wen Wee Ma et al. "LAPACT: An open-label, multicenter phase II trial of nab-paclitaxel (nab-P) plus gemcitabine (Gem) in patients (pts) with locally advanced pancreatic cancer (LAPC)." Journal of Clinical Oncology 34, n. 4_suppl (1 febbraio 2016): TPS477. http://dx.doi.org/10.1200/jco.2016.34.4_suppl.tps477.

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TPS477 Background: In pts with LAPC, more effective systemic therapies may be associated with improved local control, delay of metastasis, and overall survival (OS). The phase III MPACT trial in pts with metastatic PC demonstrated longer OS (median, 8.7 vs 6.6 mos; HR, 0.72; P < 0.001) and an ≈ 3-fold greater shrinkage of primary tumors with nab-P + Gem vs Gem alone (−22.15% vs −7.02%), raising the possibility of improved local PC control with nab-P + Gem. LAPACT will assess the efficacy and safety of nab-P + Gem in LAPC. Methods: LAPACT will enroll treatment-naive pts (planned n ≈ 110) in the United States, Canada, and Europe with Eastern Cooperative Oncology Group performance status ≤ 1, confirmed unresectable LAPC, no distant metastases, and adequate organ function. Pts with mixed-origin tumors, any other malignancy within 5 years, peripheral neuropathy grade > 1, or clinically significant ascites are ineligible. Pts will receive nab-P 125 mg/m2 + Gem 1000 mg/m2 on days 1, 8, and 15 of each 28-day cycle. Pts without progressive disease (PD) or unacceptable toxicity after 6 cycles will receive investigator’s choice of surgery, chemoradiotherapy, or continued nab-P + Gem. If a major response is observed, surgery may occur prior to completing 6 cycles of nab-P + Gem. The primary endpoint is time to treatment failure (TTF; time from first therapy dose to discontinuation due to PD, start of a new non–protocol-defined anti-cancer therapy, or death). The study design allows for 80% power at a 1-sided α of 0.05 to detect a 30% increase over the 5.1-month median TTF observed for nab-P + Gem in the MPACT study. The secondary endpoints are disease control rate (DCR) after 6 cycles, overall response rate, progression-free survival, OS, safety, and quality of life. The exploratory endpoint is correlation of changes in circulating nucleic acids with PD and treatment response. An interim DCR analysis will occur after all pts have completed 6 cycles of nab-P + Gem, discontinued therapy due to PD, died, or started a new non–protocol-defined therapy before completing 6 cycles of therapy. Enrollment is ongoing (first pt enrolled in April 2015). Clinical trial information: NCT02301143.

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Qiu, Wenli, Huifeng Zhang, Xiao Chen, Lina Song, Wenjing Cui, Shuai Ren, Yajie Wang et al. "A GPC1-targeted and gemcitabine-loaded biocompatible nanoplatform for pancreatic cancer multimodal imaging and therapy". Nanomedicine 14, n. 17 (settembre 2019): 2339–53. http://dx.doi.org/10.2217/nnm-2019-0063.

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Aim: Biomarker-targeted nanocarrier holds promise for early diagnosis and effective therapy of cancer. Materials & methods: This work successfully designs and evaluates GPC1-targeted, gemcitabine (GEM)-loaded multifunctional gold nanocarrier for near-infrared fluorescence (NIRF)/MRI and targeted chemotherapy against pancreatic cancer in vitro and in vivo. Results: Blood biochemical and histological analyses show that the in vivo toxicity of GPC1-GEM-nanoparticles (NPs) was negligible. Both in vitro and in vivo studies demonstrate that GPC1-GEM-NPs can be used as NIRF/MR contrast agent for pancreatic cancer detection. Treatment of xenografted mice with GPC1-GEM-NPs shows a higher tumor inhibitory effect compared with controls. Conclusion: This novel theranostic nanoplatform provides early diagnostic and effective therapeutic potential for pancreatic cancer.

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Timmer, J. H., T. L. van Vuure, V. Bom, C. W. van Eijk, J. de Haas e J. M. Schippers. "A scintillating GEM for 2D-dosimetry in radiation therapy". Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment 478, n. 1-2 (febbraio 2002): 98–103. http://dx.doi.org/10.1016/s0168-9002(01)01718-1.

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Selvanesan, Benson Chellakkan, Kiran Meena, Amanda Beck, Lydie Meheus, Olaya Lara, Ilse Rooman e Claudia Gravekamp. "Nicotinamide combined with gemcitabine is an immunomodulatory therapy that restrains pancreatic cancer in mice". Journal for ImmunoTherapy of Cancer 8, n. 2 (novembre 2020): e001250. http://dx.doi.org/10.1136/jitc-2020-001250.

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BackgroundTreatments for pancreatic ductal adenocarcinoma are poorly effective, at least partly due to the tumor’s immune-suppressive stromal compartment. New evidence of positive effects on immune responses in the tumor microenvironment (TME), compelled us to test the combination of gemcitabine (GEM), a standard chemotherapeutic for pancreatic cancer, with nicotinamide (NAM), the amide form of niacin (vitamin B3), in mice with pancreatic cancer.MethodsVarious mouse tumor models of pancreatic cancer, that is, orthotopic Panc-02 and KPC (KrasG12D, p53R172H, Pdx1-Cre) grafts, were treated alternately with NAM and GEM for 2 weeks, and the effects on efficacy, survival, stromal architecture and tumor-infiltrating immune cells was examined by immunohistochemistry (IHC), flow cytometry, Enzyme-linked immunospot (ELISPOT), T cell depletions in vivo, Nanostring analysis and RNAscope.ResultsA significant reduction in tumor weight and number of metastases was found, as well as a significant improved survival of the NAM+GEM group compared with all control groups. IHC and flow cytometry showed a significant decrease in tumor-associated macrophages and myeloid-derived suppressor cells in the tumors of NAM+GEM-treated mice. This correlated with a significant increase in the number of CD4 and CD8 T cells of NAM+GEM-treated tumors, and CD4 and CD8 T cell responses to tumor-associated antigen survivin, most likely through epitope spreading. In vivo depletions of T cells demonstrated the involvement of CD4 T cells in the eradication of the tumor by NAM+GEM treatment. In addition, remodeling of the tumor stroma was observed with decreased collagen I and lower expression of hyaluronic acid binding protein, reorganization of the immune cells into lymph node like structures and CD31 positive vessels. Expression profiling for a panel of immuno-oncology genes revealed significant changes in genes involved in migration and activation of T cells, attraction of dendritic cells and epitope spreading.ConclusionThis study highlights the potential of NAM+GEM as immunotherapy for advanced pancreatic cancer.

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Tschoep, K. E., V. Milani, G. Schmidt, X. Schiel, S. Abdel-Rahman, M. F. Kuhlencordt, C. Salat, V. Maier, V. Heinemann e R. D. Issels. "Gemcitabine + cisplatin (GEM+CIS) in combination with regional hyperthermia (RHT) in second-line therapy of gemcitabine-refractory metastatic pancreatic cancer". Journal of Clinical Oncology 24, n. 18_suppl (20 giugno 2006): 14073. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.14073.

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14073 Background: Our completed phase III trial comparing GEM + CIS vs. GEM alone showed good efficacy for the combination arm in 1st-line therapy (ASCO abstr. No. 1003, 2003). Based on the rationale of chemosensitization of CIS by RHT we are performing a prospective phase II study with GEM + CIS combined with RHT. Methods: Until 8/2005 12 pts with metastatic pancreatic adenocarcinoma who failed GEM-based 1st-line-therapy were enrolled in this study. One cycle consisted of GEM (1000mg/m2) on d1 followed by CIS (25mg/m2) on d2 and d4 combined with RHT (BSD system). A total of 2 blocks each of 4 cycles were given biweekly. The main endpoints were time to second progression (TTP2) and 1-year event free survival (1-yr-EFS). TTP2 and EFS were defined as time from start of 2nd-line therapy until progression of disease or death. Response (RECIST) was evaluated after 4 and 8 cycles of therapy. Results: Pt characteristics: median age 60; M:F=8:4. Median time to first progression (TTP1) was 6 months (95% CI:2–7). 8/12 pts received all 8 cycles. No toxic death and no grade 4 toxicity occurred. In 12/2005 10/12 pts were evaluable for this study. Control of disease (1CR, 2MR, 4NC) and progression (3PD) occurred in 70% and 30% respectively. The median TTP2 is 8 months (95% CI: 2–13) and the 1-yr-EFS is 32% (95% CI:3–61). 7 pts are alive at 12/2005. Conclusions: Our ongoing study (EudraCT-No 2005–003855–11) using RHT combined with GEM + CIS shows promising antitumor activity with a very encouraging TTP2 and median 1-yr-EFS in the 2nd-line treatment of GEM-refractory metastatic pancreatic cancer. [Table: see text]

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Brody, J., A. Dasgupta, C. L. Costantino, E. Kennedy, C. J. Yeo e A. K. Witkiewicz. "Correlation of HuR cytoplasmic expression in pancreatic cancer and overall patient survival when treated with gemcitabine in the adjuvant setting". Journal of Clinical Oncology 27, n. 15_suppl (20 maggio 2009): 11097. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.11097.

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11097 Background:The Hu/ELAV mRNA binding protein HuR is normally localized to the nucleus and is activated upon stress. Previously, we observed that HuR expression is predominantly cytoplasmic in aggressive forms of pancreatic ductal adenocarcinomas (PDA). Additionally, we have shown that overexpression of HuR in pancreatic cancer cell lines renders them hypersensitive to gemcitabine (GEM). GEM is the standard first line therapy used against PDA. This study was designed to determine the relationship between endogenous HuR expression levels and patient outcome. Methods: We analyzed tissue from 29 resected PDA patients who did not receive neoadjuvant therapy. We determined the intensity of cytoplasmic HuR expression. All patients received adjuvant GEM, alone or in combination with radiation therapy or other chemotherapeutics. Correlation between HuR expression levels and overall survival was evaluated. Results: The median overall survival was 20.6 months, with 18 deaths observed. Median overall survival for low HuR expression was 15.3 months. Median overall survival for high HuR expression was not reached at a follow up of 40 months. A univariate Cox regression model gives a hazard ratio of low to high HuR of 3.36 (p=0.025) [95% CI 1.09–10.35]. Adjusting for age, sex, and radiation therapy in this patient group gives an adjusted hazard ratio of 5.04 (p = 0.03) [95% CI 1.15–22.02]. This indicates a 5-fold increase in risk of death in patients with low HuR levels compared to high HuR levels among patients receiving GEM. Conclusions: This is the first report of a correlation between levels of cytoplasmic HuR expression and overall survival in GEM treated patients. Together with our previously reported experimental data, HuR is regulating the key metabolic enzyme for GEM activation (deoxycytidine kinase). Therefore, HuR is a marker for therapeutic efficacy of GEM based regimens and is a candidate target for the optimization of GEM based treatment strategies. [Table: see text] No significant financial relationships to disclose.

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Ostapoff, Katherine T., Niranjan Awasthi, Peter L. Yen, Changhua Zhang, Margaret A. Schwarz, Rolf A. Brekken e Roderich Schwarz. "Effect of NVP-BEZ235, a dual PI3K/mTOR inhibitor, on chemotherapy and antiangiogenic response in pancreatic cancer." Journal of Clinical Oncology 30, n. 4_suppl (1 febbraio 2012): 243. http://dx.doi.org/10.1200/jco.2012.30.4_suppl.243.

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243 Background: The phosphatidylinositol-3-kinase (PI3K)/AKT and mammalian target of rapamycin (mTOR) signaling pathway dysregulation is a prominent feature of pancreatic ductal adenocarcinoma (PDAC). Gemcitabine (GEM), a standard systemic treatment for PDAC, has limited clinical benefits. The present study investigated the effects of NVP-BEZ235 (BEZ235), a novel dual PI3K/mTOR inhibitor, in combination with gemcitabine and endothelial monocyte activating polypeptide II (EMAP) in experimental PDAC. Methods: Protein expression and cell proliferation were analyzed by Western blotting and WST-1 assay. Animal experiments were performed in murine xenografts. Results: BEZ235 inhibited phospho-AKT (Ser473) and phospho-mTOR (Ser2448) expression in PDAC (AsPC-1), endothelial (HUVECs) and fibroblast (WI-38) cells. NVP-BEZ235 also caused a significant dephosphorylation of downstream mTORC1 target proteins phospho-p70 S6K (Thr389) and phospho-4E-BP1 (Thr37/46). In vitro 72-hour proliferation of four PDAC cell lines was significantly inhibited by BEZ235. Additive effects on proliferation inhibition were observed in the BEZ235 and GEM combination in PDAC cells and in combination of BEZ235 or EMAP with gemcitabine in HUVECs and WI-38 cells. BEZ235, alone or in combination with GEM and EMAP, induced apoptosis in AsPC-1, HUVECs and WI-38 cells as observed by increased expression of cleaved poly (ADP-ribose) polymerase-1 (PARP-1) and caspase-3 proteins. PDAC in vivo therapy demonstrated that compared to controls (median survival: 16 days), animal survival increased after BEZ235 and EMAP therapy alone (both 21 days) and GEM monotherapy (28 days). Further increases in survival occurred in combination therapy groups BEZ235+GEM (30 days, p=0.007), BEZ235+EMAP (27 days, p=0.02), GEM+EMAP (31 days, p=0.001) and BEZ235+GEM +EMAP (33 days, p=0.004). Conclusions: BEZ235 has experimental PDAC antitumor activity in vitro and in vivo that can be enhanced in combination with cytotoxic (GEM) and antiendothelial (EMAP) agents. These findings demonstrate advantages of combination therapy strategies targeting multiple pathways in pancreatic cancer treatment.

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Loehrer, Patrick J., Yang Feng, Higinia Cardenes, Lynne Wagner, Joanna M. Brell, David Cella, Patrick Flynn et al. "Gemcitabine Alone Versus Gemcitabine Plus Radiotherapy in Patients With Locally Advanced Pancreatic Cancer: An Eastern Cooperative Oncology Group Trial". Journal of Clinical Oncology 29, n. 31 (1 novembre 2011): 4105–12. http://dx.doi.org/10.1200/jco.2011.34.8904.

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Purpose The purpose of this trial was to evaluate the role of radiation therapy with concurrent gemcitabine (GEM) compared with GEM alone in patients with localized unresectable pancreatic cancer. Patients and Methods Patients with localized unresectable adenocarcinoma of the pancreas were randomly assigned to receive GEM alone (at 1,000 mg/m2/wk for weeks 1 to 6, followed by 1 week rest, then for 3 of 4 weeks) or GEM (600 mg/m2/wk for weeks 1 to 5, then 4 weeks later 1,000 mg/m2 for 3 of 4 weeks) plus radiotherapy (starting on day 1, 1.8 Gy/Fx for total of 50.4 Gy). Measurement of quality of life using the Functional Assessment of Cancer Therapy–Hepatobiliary questionnaire was also performed. Results Of 74 patients entered on trial and randomly assigned to receive GEM alone (arm A; n = 37) or GEM plus radiation (arm B; n = 34), patients in arm B had greater incidence of grades 4 and 5 toxicities (41% v 9%), but grades 3 and 4 toxicities combined were similar (77% in A v 79% in B). No statistical differences were seen in quality of life measurements at 6, 15 to 16, and 36 weeks. The primary end point was survival, which was 9.2 months (95% CI, 7.9 to 11.4 months) and 11.1 months (95% CI, 7.6 to 15.5 months) for arms A and B, respectively (one-sided P = .017 by stratified log-rank test). Conclusion This trial demonstrates improved overall survival with the addition of radiation therapy to GEM in patients with localized unresectable pancreatic cancer, with acceptable toxicity.

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Kanji, Zaheer S., Alicia M. Edwards, Margaret T. Mandelson, Bruce Lin, Kasra Badiozamani, Goubin Song, Adnan Alseidi et al. "Gemcitabine/taxane adjuvant therapy in resected pancreatic cancer: A signal of improved survival?" Journal of Clinical Oncology 35, n. 4_suppl (1 febbraio 2017): 392. http://dx.doi.org/10.1200/jco.2017.35.4_suppl.392.

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392 Background: Gemcitabine-taxane combination chemotherapy has demonstrated a survival benefit in metastatic pancreatic cancer (PC). We present our experience with gemcitabine/docetaxel (gem/tax) based adjuvant treatment (Rx) following curative intent surgery. Methods: Patients with upfront resectable PC from January 1, 2010 to December 31, 2015 were identified from our institutional database and tumor registry. We included resected patients who received gem/tax as initial Rx administered exclusively at our institution with or without chemoradiation (CRTx). Patients were excluded if they died or recurred prior to Rx or received neoadjuvant Rx. Survival was estimated by Kaplan-Meier methods and prognostic factors identified by Cox regression. Results: Of 185 eligible patients, 58 met study criteria. Characteristics included: median age of diagnosis 64.9 years, female gender 56.9%, Whipple procedure 69% and R1 resection in 55.2%%. Tumour characteristics included: median size 28.0mm, poor differentiation 53.5% and AJCC stage 2A/2B 27.6%/67.2%. Patients completing ≥ 80% of 24 week Rx was 89.7% (n = 52). Of those patients, 71.2% received post gem/tax CRTx. With a 51.2 month median follow-up (95%CI: 37.1-55.7), median disease-free survival (DFS) and overall survival (OS) were 35 months (95%CI: 20.7-NR) and 52.3 months (95%CI: 27.4-NR), respectively. Five year OS was 49.5% (95%CI: 33.7-63.4). Patients receiving CRTx (n = 37) had a superior OS compared to patients who only completed gem/tax Rx (n = 15)(61.5 vs. 26.7 months, p = 0.04). Prognostic variables impacting OS on multivariate analysis (HR, 95%CI) included: margin status (4.55, 1.46-14.2, p = 0.01), AJCC stage (10.9, 2.46-47.9, p = 0.002) and administration of CRTx (0.08, 0.03-0.24, p < 0.000). Variables impacting DFS included: AJCC stage (3.29, 1.15-9.41, p = 0.03), tumour size (2.59, 1.11-6.04, p = 0.03) and administration of CRTx (0.23, 0.09-0.56, p = 0.001). Conclusions: In this select cohort of resected PC patients with adverse pathologic features, adjuvant gem/tax with or without CRTx is feasible with favorable DFS and OS. These findings support further prospective studies of gem/taxane-based adjuvant Rx in PC.

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Nahar, Kazi Jannatun, David Chan, Anubhav Mittal, Jaswinder S. Samra, Thomas Hugh, Connie Irene Diakos, Stephen John Clarke e Nick Pavlakis. "Adjuvant therapy in pancreatic adenocarcinoma: A systemic review and meta-analysis." Journal of Clinical Oncology 34, n. 4_suppl (1 febbraio 2016): 330. http://dx.doi.org/10.1200/jco.2016.34.4_suppl.330.

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330 Background: The “optimal” adjuvant treatment in pancreatic cancer remains undetermined. Chemotherapy (chemo) such as gemcitabine (Gem), 5-fluorouracil (5-FU) and chemo-radiotherapy (chemoRT) with either Gem or 5-FU have been investigated in trials. We performed a systematic review and meta-analysis to determine the overall efficacy of adjuvant treatment. Methods: We searched databases (PubMed, Medline, Cochrane database) and major conference proceedings up until August 2015 for randomized trials comparing chemo or chemoRT versus (vs) observation, two different chemo regimens and chemoRT vs chemo. Primary end point was overall survival (OS); secondary end points were relapse free survival (RFS), grade 3/4 toxic effects and quality of life (QoL). We performed meta-analysis as per the PRISMA guidelines; hazard ratios (HR) for OS and RFS were pooled with random-effects modelling. Results: Fifteen trials were identified evaluating 4348 patients. For trials comparing chemo to observation (7 trials, n = 1383) the OS HR was 0.77 (95% CI 0.67-0.89, p = 0.001) and PFS HR 0.73 (95% CI 0.53-1.01, p = 0.06) both favouring chemo. For trials investigating Gem (2 trials, n = 472), OS was improved with HR 0.76 (95% CI 0.63 -0.92, p = 0.006) as was RFS (HR 0.56, 95% CI 0.46-0.68, p < 0.00001). For trials investigating agents other than Gem (5 trials, n = 911), OS was improved with HR 0.79 (95% CI 0.63-0.99, p = 0.04), but RFS was not (2 trials only, HR 1.00, 95% CI 0.73-1.37, p = 0.99). Five trials (n = 1832) compared different chemo regimens to Gem in each case; pooled OS HR was 0.90 (95% CI 0.65-1.25, p = 0.54) and RFS HR 0.88 (95% CI 0.67-1.15, p = 0.35). Insufficient data was available to pool grade 3/4 toxicity for chemo vs observation trials; no significant difference was found in incidence of overall grade 3/4 toxicity for trials comparing two chemo regimens (OR 0.98, 95% CI 0.39-2.47, p = 0.96). QoL data was available in 3 trials (ESPAC-1, ESPAC-3, CapRi) with no significant differences noted. Conclusions: Adjuvant chemo vs no chemo for resected pancreatic adenocarcinoma improves OS and RFS. Adjuvant ChemoRT vs no treatment is not beneficial. Overall, novel chemo regimens have not been shown to be superior to Gem. Reporting of QoL is inadequate to make any conclusion.

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Addeo, Raffaele, Michele Caraglia, Sergio Bellini, Alberto Abbruzzese, Bruno Vincenzi, Liliana Montella, Antonio Miragliuolo et al. "Randomized Phase III Trial on Gemcitabine Versus Mytomicin in Recurrent Superficial Bladder Cancer: Evaluation of Efficacy and Tolerance". Journal of Clinical Oncology 28, n. 4 (1 febbraio 2010): 543–48. http://dx.doi.org/10.1200/jco.2008.20.8199.

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Purpose Approximately 30% to 40% patients with a superficial bladder cancer treated with Bacille Calmette-Guerin (BCG) or epirubicin do not respond; of the initial responders, 35% have a relapse within 5 years. We compare the therapeutic efficacy and toxicity of intravescical infusions of gemcitabine (GEM) with mitomycin (MMC) in patients with a recurrent superficial bladder cancer. Patients and Methods Patients with a history of a previously treated, recurrent Ta-T1, G1-G3 bladder transitional cell carcinoma were enrolled in the study. The patients received a 6-week course of GEM infusions or 4-week course of MMC. In both arms, for the initial responders who remained free of recurrences, maintenance therapy consisted of 10 monthly treatments during the first year. Results A total of 120 patients were enrolled and randomly assigned to either the MMC or GEM treatment arm. At the end of the study, 109 patients (55 in MMC and 54 in GEM) were assessable. The median duration of follow-up was 36 months for either arm. In the GEM arm, 39 (72%) of 54 patients remained free of recurrence versus 33 (61%) of 55 in MMC arm. Among patients with recurrences, 10 in the MMC arm and six in the GEM arm also had a progressive disease by stage. The incidence of chemical cystitis in the MMC arm was statistically higher than in the GEM arm (P = .012). Conclusion This study demonstrates that GEM has better efficacy and lower toxicity than MMC; therefore, GEM appears as a logical candidate for intrabladder therapy in patients with refractory transitional cancer.

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Yoshitomi, Hideyuki, Hiroaki Shimizu, Hiroyuki Yoshidome, Masayuki Ohtsuka, Atsushi Kato, Katsunori Furukawa, Tsukasa Takayashiki et al. "A randomized phase II trial of adjuvant chemotherapy with S-1 versus S-1 and gemcitabine (GS) versus gemcitabine alone (GEM) in patients with resected pancreatic cancer (CAP-002 study)." Journal of Clinical Oncology 31, n. 15_suppl (20 maggio 2013): 4056. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.4056.

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4056 Background: Although the adjuvant therapy using GEM is now the standard therapy for patients with resected pancreatic cancer (PC), the prognosis still remains poor. Resent study demonstrated the non-inferiority of S-1 and superiority of GS to GEM with respect to progression free survival in patients with unresectable pancreatic cancer. Methods: Patients with invasive ductal PC who underwent radical surgery were enrolled. After stratification for R0/1, stage and institution, patients were randomized to receive GEM (GEM 1g/ m2, iv, d1, 8, and 15, q4w X12), S-1 (80/100/120mg/day based on BSA, po, d1-14, q3w X 16) or GS (S-1 60/80/100mg/day based on BSA po, d1-14 plus GEM 1g/ m2, iv, d8, 15, q3w X 16) within 8weeks after operation. Eligibility included histological residual tumor (R) 0 or 1, and no previous chemo- or/and radiation therapy. Primary endpoint was 2y disease free survival (DFS) rate and secondary endpoints included overall survival (OS), and safety. Results: Between January 2007 and October 2010, 96 patients were randomized into the three arms of the trial (32 pts to each group). Patients’ characteristics were well balanced (GEM/S-1/GS) with regard to age (66/67/66y), tumor location (head 66/69/75%), tumor status (T3+4 88/78/91%), and nodal status (positive 75/69/75%). Until November 2012, 74 events (77%) have occurred for DFS. Two year DFS rate was 24.2%, 28.1% and 34.4% in GEM, S-1 and GS, respectively and there was no significant difference between groups. The median OS was 21m in GEM, 26m in S-1 and 27.9m in GS (Log rank test: N.S.). Grade 3/4 toxicities in GEM/S-1/GS were hematological 63/10/74% and non-hematological 17/10/23%, respectively. No treatment related death was observed during the study. Conclusions: S-1 and GS provided similar efficacy to GEM as the adjuvant chemotherapy for resected PC. According to the results, S-1 and GS is the adequate combination for phase III trial to examine the efficacy of adjuvant chemotherapy for PC. Clinical trial information: UMIN000002000.

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Miron, Benjamin, Elizabeth A. Handorf, Kevin Zarrabi, Matthew R. Zibelman, Pooja Ghatalia, Fern Anari, Elizabeth R. Plimack e Daniel M. Geynisman. "Influence of first-line chemotherapy regimen on survival outcomes of patients with advanced urothelial carcinoma who receive second-line immunotherapy." Journal of Clinical Oncology 39, n. 15_suppl (20 maggio 2021): 4535. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.4535.

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4535 Background: Treatment of advanced urothelial carcinoma (mUC) has improved following approvals of PD-1/PD-L1 inhibitors. Platinum chemotherapy remains the standard-of-care in the first-line (1L). Cisplatin (Cis) regimens are accepted to be superior to carboplatin (Carbo) regimens for patients (pts) who are Cis-eligible. We sought to evaluate if differences in efficacy of 1L Cis vs. Carbo have meaningful impact on overall survival (OS) in the era of second-line (2L) immunotherapy (IO). Methods: We conducted a retrospective, observational cohort study to compare OS for pts treated with 1L Cis or Carbo combined with gemcitabine (Gem) followed by 2L IO using patient-level data from the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database. Pts included were diagnosed with mUC between 9/1/2015 and 9/15/2020. 2L IO was defined as single-agent atezolizumab, avelumab, durvalumab, nivolumab, or pembrolizumab. OS was calculated from start of 1L and 2L therapy and compared using Kaplan-Meier curves. Time to 2L IO was calculated from start of 1L to start of IO. Adjusted OS was calculated using multivariable Cox regression models, adjusting for age, gender, race, ECOG performance status, primary site, prior cystectomy, smoking status, and year of diagnosis. Results: A total of 1882 pts were included, 924 (49.1%) received Gem/Cis and 958 (50.9%) received Gem/Carbo in 1L. A similar percentage of pts did not receive any 2L therapy following Gem/Cis (46.4%) or Gem/Carbo (46.0%). Our analysis focused on the 780 pts (41.4%) who received 2L IO—381 after Gem/Cis and 399 after Gem/Carbo. Median follow-up time for the group was 35 months (mo). Pts in the Gem/Cis cohort were younger, had better performance status and lower incidence of upper tract disease (Table). OS from start of 1L therapy was numerically longer in pts who received Gem/Cis compared to Gem/Carbo on unadjusted (median 18.0 v 16.2 mo, p = 0.06) and adjusted analyses (HR = 0.83, 95% CI 0.69-1.00, p = 0.055) but neither result was statistically significant. Time to 2L IO was longer for pts receiving Gem/Cis (6.5 mo) vs Gem/Carbo (5.5 mo, p = 0.008). Survival time on 2L IO did not differ significantly by 1L regimen (Gem/Cis 8.0 mo vs Gem/Carbo 8.2 mo p = 0.36). Conclusions: Real world data suggests that in pts with mUC who are able to receive second-line IO, the choice of first-line platinum chemotherapy may not provide a distinguishable OS benefit. Despite methodologic limitations of this data, a greater focus in discussions with patients on toxicity associated with cisplatin vs carboplatin may be warranted.[Table: see text]

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Rogers, Jane Elizabeth, Lindsey Law, D. Van Nguyen, Wei Qiao, Milind M. Javle, Ahmed Omar Kaseb e Rachna T. Shroff. "Second-line systemic treatment for advanced cholangiocarcinoma." Journal of Clinical Oncology 32, n. 3_suppl (20 gennaio 2014): 371. http://dx.doi.org/10.1200/jco.2014.32.3_suppl.371.

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371 Background: Five-year survival for advanced cholangiocarcinoma (aCC) is reported at 5-10%. For advanced, unresectable patients, gemcitabine plus platinum (GEM-P) combination chemotherapy is common practice as first-line treatment with progression free survival (PFS) of 8 months and overall survival (OS) of 11.7 months. Data regarding chemotherapy treatment after first-line progression is limited. Methods: We performed a retrospective chart review of patients with aCC from 1/1/2009 to 12/31/2012 who received second-line chemotherapy at M.D. Anderson Cancer Center (MDACC). Median PFS was the primary endpoint. Secondary objectives included disease control rate (complete response + partial response + stable disease) and OS. Inclusion criteria: aCC diagnosis, progression on first-line therapy, and reimaging studies at MDACC. Exclusion criteria: patients who received localized treatment for aCC prior to second-line therapy or consolidative chemoradiation, mixed histology tumors, and those with a history of another malignancy. Results: 56 patients were identified, with the majority having intrahepatic aCC (95%). 80% of patients received gemcitabine based first-line treatment (GEM-P +/- erlotinib, GEM monotherapy). Second-line systemic treatment included GEM-P (19.6%), GEM + fluoropyrmidine (GEM-FU) (28.6%), fluoropyrmidine combination (FU-combo) (37.5%), and other consisting of chemotherapy or biotherapy monotherapy or combination (14.3%). Total median PFS was 2.7 months (95% CI = 2.3 to 3.8). Disease control rate was 50% with a median OS of 13.8 months (95% CI = 12 to19.3). No significant difference in PFS or OS was identified between the four second line treatment groups. A higher CA 19-9 at the start of second line treatment correlated with a worse survival (p= <0.01). Conclusions: This retrospective study revealed a 50% disease control rate, median PFS of 2.7 months, and a potential for improvement in OS in patients who received second line systemic treatment. Agents that may be considered include GEM + FU, FU-combination therapy, or GEM-P if not given first line.

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Raafat, Hesham. "Biological therapy in severe asthma: A gem or a jam". Egyptian Journal of Bronchology 10, n. 1 (2016): 1. http://dx.doi.org/10.4103/1687-8426.176658.

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Cercek, A., M. Gollub e L. Saltz. "Gemcitabine (gem) as salvage therapy in metastatic colorectal adenocarcinoma (mCRC)." Journal of Clinical Oncology 29, n. 15_suppl (20 maggio 2011): e14135-e14135. http://dx.doi.org/10.1200/jco.2011.29.15_suppl.e14135.

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Dieguez, Gabriela, Samantha Tomicki, David DeStephano e Paul Cockrum. "Trends in use of one, two, and three-line NCCNcategory 1 regimens among Medicare fee-for-service (FFS) patients receiving treatment for metastatic pancreatic cancer." Journal of Clinical Oncology 39, n. 28_suppl (1 ottobre 2021): 297. http://dx.doi.org/10.1200/jco.2020.39.28_suppl.297.

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297 Background: There is limited research evaluating the share of patients (pts) with metastatic pancreatic cancer (m-PANC) treated according to NCCN guidelines. Methods: We identified pts with m-PANC using ICD-10 diagnosis codes in the 2016-2019 Medicare Parts A/B/D 100% Research Identifiable Files. Study pts had 2+ claims with a pancreatic cancer diagnosis and Medicare FFS coverage for 6 months pre- and 3 months post-metastatic disease diagnosis. A line of therapy (LOT) was assigned based on the order and number of therapies used. Pts with one, two, or three LOTs were defined as treated according to NCCN Category 1 guidelines if, in each LOT, pts used one of the following regimens: FOLFIRINOX (FFX), gemcitabine/nab-paclitaxel (gem/nab), gemcitabine + erlotinib, gemcitabine monotherapy, or 5-FU + leucovorin + liposomal irinotecan. Multi-drug LOTs were excluded from the analysis. Results: We identified 31,782 pts with m-PANC. 21,304 received one LOT, 7,352 received two LOTs, and 3,126 received three LOTs between 2016 and 2019. Among pts who received one or two LOTs, a higher portion were treated according to NCCN Category 1 guidelines in 2019 (72% and 43%, respectively) than in 2016 (64% and 33%, respectively). Among pts who received three LOTs, a higher portion were treated according to NCCN Category 1 guidelines in 2019 (17%) than in 2017 (12%); too few pts were treated in 2016 to make a comparison. From 2016 to 2019, FFX had the largest increase in share of pts receiving only one NCCN Category 1 LOT (11% to 27%) and gem-mono had the largest decrease (30% to 17%). Among pts receiving two NCCN Category 1 LOTs, gem/nab to liposomal irinotecan sequences had the largest increase in share of pts (18% to 32%) and gem/nab to FFX had the largest decrease (17% to 10%). Among pts receiving three NCCN Category 1 LOTs, patient share for FFX to gem/nab to Liposomal irinotecan was 35% in 2019, while gem/nab to FFX to Liposomal was 8%; pt counts in earlier years were too small to calculate patient share. Conclusions: The use of NCCN Category 1 therapies increased consistently from 2016 to 2019 among pts that received one, two, and three lines of therapy. FFX drove increases in NCCN Category 1 utilization among patients receiving one line of therapy, and gem/nab to liposomal irinotecan sequences were the primary drivers of the increase among patients receiving two lines of therapy. FFX to gem/nab to liposomal irinotecan was the primary driver of increase among patients receiving three lines of therapy.

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Awasthi, N., M. A. Schwarz, P. L. Yen e R. Schwarz. "Augmenting chemotherapy response through EMAP II combination in experimental pancreatic cancer." Journal of Clinical Oncology 29, n. 4_suppl (1 febbraio 2011): 294. http://dx.doi.org/10.1200/jco.2011.29.4_suppl.294.

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294 Background: Gemcitabine (Gem), the most active drug for locally advanced, non-operable and metastatic PDAC, has limited benefits as single agent or in combination. Endothelial monocyte activating polypeptide II (EMAP, E) enhances Gem effects in PDAC. We evaluated the antitumor activities of EMAP in combination with doxorubicin (Dox) or docetaxel (DT) in PDAC. Methods: In vitro cell proliferation, protein expression and apoptosis were analyzed by WST-1 assay, Western blotting and FACS analysis. In vivo local tumor growth and animal survival experiments were performed in murine xenografts. Results: In vitro PDAC cell proliferation was not affected by EMAP, compared to a small inhibition by Dox, DT and Gem. EMAP combination to these agents did not increase the antiproliferative effects. In endothelial cells (ECs), EMAP, Dox, DT and Gem all inhibited proliferation (59, 79, 96 and 85% at 10 μM, respectively); addition of EMAP caused additive antiproliferative effects. In PDAC cells, no agent caused measurable apoptosis, but in ECs all agents either alone or in combination increased the apoptosis. In vivo, Dox, DT, Gem and EMAP all decreased local tumor growth, and addition of EMAP enhanced inhibitory effects of DT and Gem, but not of Dox (92, 63, 60, 42, 73, 85 and 68 % inhibition after Dox, DT, Gem, E, Dox+E, DT+E and Gem+E, respectively); DT followed by Gem led to 72% inhibition without EMAP, and to 99% with EMAP (p=0.001). Inhibition of intra-tumoral proliferative activity and increase of apoptotic index were enhanced in all EMAP combination groups. Compared to controls (median survival: 21 days), EMAP (20 d) had no, but Dox (31 d) and DT (35 d) had extended survival benefit. EMAP enhanced the DT effect (44 d, p=0.009) but not that of Dox (31 d, p=0.04). In a sequential therapy experiment, median survival after controls, Gem, DT, Gem followed by DT, DT followed by Gem, Gem+E, DT+E, Gem/DT+E and DT/Gem+E was 17, 25, 29, 39, 39, 28, 35, 34 and 41 days, respectively. Conclusions: The antiendothelial agent EMAP enhances antitumor effects of not just gemcitabine. Therefore, combination approaches with EMAP-like agents could render other drugs such as taxanes or their doublets sufficiently effective for clinical applications in PDAC therapy. No significant financial relationships to disclose.

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Ramanathan, Ramesh K., Peter Lee, John E. Seng, Stephen Patrick Anthony, Peter J. Rosen, Raul R. Mena, Vincent J. Picozzi et al. "Phase II study of induction therapy with gemcitabine and nab-paclitaxel followed by consolidation with mFOLFIRINOX in patients with metastatic pancreatic cancer." Journal of Clinical Oncology 32, n. 3_suppl (20 gennaio 2014): 224. http://dx.doi.org/10.1200/jco.2014.32.3_suppl.224.

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224 Background: FOLFIRINOX or NabP-Gem are now standard mPC regimens.The optimal sequence is not known.This phase II study evaluated the feasibility of NabP-Gem followed by FOLFIRINOX. Methods: Eligible pts had evidence of untreated mPC, ECOG 0-1 and adequate organ function. Pts received Nab-P (125 mg/m2) and Gem (1000 mg/ m2) weekly x 3 (Induction ) every 4 weeks for upto 6 cycles. FOLFIRINOX, q2 weeks (Consolidation regimen) was initiated after 6 cycles of the Induction regimen, or earlier in case of progression, and given for a maximum of 6 months (12 cycles). mFOLFIRINOX (NEJM, 364:1817-25: 2011) has been modified with growth factor prophylaxis and omission of bolus 5FU. One endpoint is to increase 1 year survival to > 70%, (n=30, 95% CI is +/- 20%). Results: Accrual goals have been met (n=31). The M/F ratio is 55%/45%, median is 66 years. In 23 pts with elevated baseline CA19-9 levels treated with NabP-Gem, 83% had a > 90% decrease. The response rate with the NabP-Gem regimen is 43%. Selected therapy related Grade > 3 adverse events during the course of both NabP-Gem and FOLFIRINOX therapy are: neutropenia (39%), fatigue (32%), anemia (19%), thrombocytopenia (16%), thromboembolic events (3%), peripheral neuropathy (16%), leukopenia (16%), nausea (3%), vomiting (3%), diarrhea (7%), and neutropenic fever (3%). During the course of NabP-Gem, 14 dose reductions and four dose delays were seen. Two pts had early progression at cycle 4 or less and were switched to the Consolidation regimen. Seventy one % (22/31) of pts went on to receive FOLFIRINOX (4 pts still on study), 4 received FOLFIRI, and one pt received FOLFOX as Consolidation therapy. One-year survival is projected to be 50-60%. Conclusions: The induction NabP-Gem regimen shows evidence of substantial activity similar to published reports (JCO.29:4548-54: 2011). The induction-consolidation strategy is feasible in selected patients. Cumulative side effects predominantly fatigue and neuropathy will require appropriate dose reductions or treatment breaks. (Supported by the Seena Magowitz foundation). Clinical trial information: NCT01488552.

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Zhang, Xia, Rikiya Taoka, Dage Liu, Yuki Matsuoka, Yoichiro Tohi, Yoshiyuki Kakehi e Mikio Sugimoto. "Knockdown of RRM1 with Adenoviral shRNA Vectors to Inhibit Tumor Cell Viability and Increase Chemotherapeutic Sensitivity to Gemcitabine in Bladder Cancer Cells". International Journal of Molecular Sciences 22, n. 8 (15 aprile 2021): 4102. http://dx.doi.org/10.3390/ijms22084102.

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RRM1—an important DNA replication/repair enzyme—is the primary molecular gemcitabine (GEM) target. High RRM1-expression associates with gemcitabine-resistance in various cancers and RRM1 inhibition may provide novel cancer treatment approaches. Our study elucidates how RRM1 inhibition affects cancer cell proliferation and influences gemcitabine-resistant bladder cancer cells. Of nine bladder cancer cell lines investigated, two RRM1 highly expressed cells, 253J and RT112, were selected for further experimentation. An RRM1-targeting shRNA was cloned into adenoviral vector, Ad-shRRM1. Gene and protein expression were investigated using real-time PCR and western blotting. Cell proliferation rate and chemotherapeutic sensitivity to GEM were assessed by MTT assay. A human tumor xenograft model was prepared by implanting RRM1 highly expressed tumors, derived from RT112 cells, in nude mice. Infection with Ad-shRRM1 effectively downregulated RRM1 expression, significantly inhibiting cell growth in both RRM1 highly expressed tumor cells. In vivo, Ad-shRRM1 treatment had pronounced antitumor effects against RRM1 highly expressed tumor xenografts (p < 0.05). Moreover, combination of Ad-shRRM1 and GEM inhibited cell proliferation in both cell lines significantly more than either treatment individually. Cancer gene therapy using anti-RRM1 shRNA has pronounced antitumor effects against RRM1 highly expressed tumors, and RRM1 inhibition specifically increases bladder cancer cell GEM-sensitivity. Ad-shRRM1/GEM combination therapy may offer new treatment options for patients with GEM-resistant bladder tumors.

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Awasthi, N., P. L. Yen, M. A. Schwarz e R. Schwarz. "Activity of a novel dual PI3-kinase/mTOR inhibitor NVP-BEZ235 to enhance antitumor activities of gemcitabine and EMAP II in pancreatic cancer." Journal of Clinical Oncology 29, n. 4_suppl (1 febbraio 2011): 255. http://dx.doi.org/10.1200/jco.2011.29.4_suppl.255.

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255 Background: Gemcitabine (Gem, G) has limited benefits as single agent or in combination for pancreatic ductal adenocarcinomas (PDACs). The phosphatidylinositol-3-kinase (PI3K)/AKT and mammalian target of rapamycin (mTOR) signaling pathways are frequently dysregulated in diverse human cancers including PDAC. NVP-BEZ235 (BEZ, B) is a novel dual PI3K/mTOR inhibitor that has been shown to have antitumor activity in multiple tumor types. Endothelial monocyte activating polypeptide II (EMAP, E) is an antiendothelial and antiangiogenic agent that enhances Gem and docetaxel activity in PDAC. We tested the combination benefits of BEZ and Gem in addition to EMAP in experimental PDAC. Methods: In vitro cell proliferation and protein expression were analyzed by WST-1 assay and Western blotting. In vivo animal survival experiments were performed in NOD-SCID PDAC xenografts. Results: Cultured cells of PDAC (AsPC-1), endothelial (HUVECs), and fibroblast origin (WI-38) all expressed AKT and mTOR protein. BEZ inhibited in vitro cell proliferation of AsPC-1 and HUVECs cells, with some additive effects in combination with Gem or EMAP, after 72 hours of incubation. In AsPC-1, treatment of BEZ (100 nM), Gem (100 nM) and EMAP (1 μM) caused 34, -7, -16, 62, 51, 3, and 59 percent inhibition in proliferation in the B, G, E, B+G, B+E, G+E and B+G+E groups. In HUVECs, percent inhibition in proliferation was 35, 33, 15, 55, 35, 31 and 53 in the B, G, E, B+G, B+E, G+E and B+G+E groups, respectively. Compared to controls (median survival: 16 days), an animal survival increase after BEZ and EMAP therapy alone (both 21 days) and Gem therapy alone (28 d) was observed. Further increases in survival occurred in combination therapy groups B+G (30 d, p=0.007), B+E (27 d, p=0.02), G+E (31 d, p=0.001) and B+G+E (33 d, p=0.004). Conclusions: Bez has experimental PDAC antitumor activity in vitro and in vivo that is further enhanced by combination of Gem and EMAP. These findings demonstrate advantages of combination therapy strategies targeting multiple pathways in pancreatic cancer treatment. No significant financial relationships to disclose.

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Palacio, Sofia, Ikechukwu Immanuel Akunyili, Vinicius Ernani, Jessica Macintyre, Jaime R. Merchan, Terri Pollack, Isildinha Reis, Maria H. Restrepo, Caio Max S. Rocha Lima e Peter Joel Hosein. "Gemcitabine (Gem) and nab-paclitaxel (nab-P) in patients (pts) with refractory advanced pancreatic cancer." Journal of Clinical Oncology 33, n. 3_suppl (20 gennaio 2015): 413. http://dx.doi.org/10.1200/jco.2015.33.3_suppl.413.

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413 Background: The combination of nab-P and Gem improves survival compared to Gem alone in first-line therapy of metastatic pancreatic cancer. Efficacy data with this doublet in previously treated pts are scant. Our group presented preliminary results on 10 pts treated with this two-drug combination in the second and third line setting and herein present updated data on 59 pts. Methods: This IRB approved analysis identified all pts diagnosed with advanced refractory pancreatic cancer, treated with second-line Gem and nab-P at University of Miami and Sylvester Comprehensive Cancer Center between September 2010 and June 2014. Response by RECIST, CA19-9, and symptomatic improvement were assessed. Progression-free survival (PFS) and overall survival (OS) were calculated from the start of Gem + nab-P and were analyzed using the Kaplan-Meier method. Clinical benefit was defined as the percentage of patients with a partial response (PR) or stable disease (SD). Results: Data from59 pts were analyzed. The median age was 60; 55% were male; 54% received Gem + nab-P as second line therapy and 46% received it as third-line or beyond. Five (10%) pts had confirmed PR, 23 (47%) SD and 21 (43%) progressed. Among the 31 (52%) pts who received prior Gem, 18 (58%) had clinical benefit, 3 PR and 15 SD. The median OS was 3.9 months. The median PFS was 3 months. Toxicity appears similar to what has been reported on the MPACT trial with the combination. Conclusions: The clinical benefit seen withGem and nab-P in this group of pretreated pancreatic cancer pts suggests that it can be considered as an option. Additionally, prior Gem treatment appears not to decrease Gem and nab-P benefit in this population. Since nab-P monotherapy has modest activity in pre-treated pancreatic cancer pts, our data suggests a positive interaction between Gem and nab-P that may overcome resistance to Gem. [Table: see text]

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Miyata, Yasuyoshi, Kensuke Mitsunari, Akihiro Asai, Tomohiro Matsuo, Kojiro Ohba e Hideki Sakai. "Human antigen R as a predictive marker for response to gemcitabine-based chemotherapy in advanced cisplatin-resistant urothelial cancer." Journal of Clinical Oncology 34, n. 2_suppl (10 gennaio 2016): 421. http://dx.doi.org/10.1200/jco.2016.34.2_suppl.421.

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421 Background: In patients with advanced urothelial cancer (UC), a combined therapy of cisplatin (CDDP) and gemcitabine (GEM) is the most commonly used first (1st)-line systematic chemotherapy. Although no regimen for CDDP-resistant UC has been established, GEM-based regimens are often used in these patients. In other cancers, HuR status in cancer cells is closely associated with response to GEM. The aim of this study was to establish the predictive value of HuR expression for disease progression and survival in UC patients treated with GEM-based regimens as 1st or second (2nd)-line chemotherapy. Methods: Fifty patients with advanced UC were included in the study. As 1st-line chemotherapy, MVEC (methotrexate, vinblastine, epirubicin, and CDDP) and GC therapy were performed in 34 (68.0%) and 16 patients (32.0%), respectively. After progression, 45 patients (90.0%) were treated with combined GEM and paclitaxel (PTX) therapy, and 5 patients (10.0%) were treated with GEM monotherapy. Cytoplasmic and nuclear Human antigen R (HuR) expression was evaluated using immunohistochemical techniques. The relationships between HuR expression and local response and outcome were analyzed. Results: In 1st-line chemotherapy, no anti-cancer effects were associated with nuclear or cytoplasmic HuR expression. In 2nd-line chemotherapy, although nuclear HuR expression also had no significant relationship to anti-cancer effects, local tumor response was significantly better if there was positive cytoplasmic HuR expression (P = 0.002). Multivariate analyses revealed that cytoplasmic HuR expression was a significant predictive marker for longer overall survival (hazard ratio, 0.22; 95% confidential interval, 0.09–0.56; P = 0.001). There is no significant relationship between nuclear HuR expression and parameters of anti-cancer effects. Conclusions: Cytoplasmic HuR expression is a significant predictive marker of response to GEM-based chemotherapy in CDDP-resistant UC. Despite limitations of a small retrospective study, our results might have important information to discuss the treatment strategies and warrant further basic and clinical research.

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Reni, Michele, Hanno Riess, Eileen Mary O'Reilly, James Andrew Reeves, Elena Chiorean, Thomas J. George, Werner Scheithauer et al. "Concordance between independent and investigator assessment of disease-free survival (DFS) in the APACT trial." Journal of Clinical Oncology 38, n. 15_suppl (20 maggio 2020): 4618. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.4618.

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4618 Background: APACT was a phase III trial of adjuvant nab-paclitaxel + gemcitabine ( nab-P + Gem) vs Gem alone in patients with resected pancreatic cancer (PC) and the first adjuvant PC trial to use independently assessed DFS as the primary endpoint (DFS by investigator review was a prespecified sensitivity analysis). We examined concordance between independent and investigator DFS review. Methods: For the independent assessment, reviewers determined recurrence by computed tomography or magnetic resonance imaging but were blinded to treatment and clinical data. Investigator-assessed DFS was based on all available data. Concordance was summarized by κ statistics. Patients who did not have recurrence or were alive were censored at the last tumor assessment date with disease-free status or the randomization date if the last tumor assessment with disease-free status was missing. Patients who received new anticancer therapy or cancer-related surgery prior to recurrence or death were censored at the date of last tumor assessment with disease-free status prior to the start of new anticancer therapy or cancer-related surgery or the randomization date if the last tumor assessment date with disease-free status prior to the start of subsequent new anticancer therapy or cancer-related surgery was missing. All censoring rules were the same for analysis of DFS by independent and investigator review. Results: Median DFS by independent review was 19.4 ( nab-P + Gem) vs 18.8 (Gem) months (hazard ratio [HR] 0.88; 95% CI, 0.73 - 1.06; P = 0.18); median investigator-assessed DFS was 16.6 ( nab-P + Gem) vs 13.7 (Gem) months (HR 0.82; 95% CI, 0.69 - 0.97; nominal P = 0.017). Moderate concordance was found between independent- and investigator-assessed DFS (Table); similar results were observed in the nab-P + Gem (concordance, 78%; κ coefficient, 0.56) and Gem alone (concordance, 76%; κ coefficient, 0.53) arms. Conclusions: The results reflect the complexities of defining the recurrence timepoint accurately and suggest that radiological review in the absence of clinical context is suboptimal for recurrence detection in resected PC. These findings may inform future clinical trial design. Registration: EudraCT (2013-003398-91); ClinicalTrials.gov (NCT01964430). Clinical trial information: NCT01964430 . [Table: see text]

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Idrees, Kamran, Alexander A. Parikh, Lauren McLendon Postlewait, Sharon M. Weber, Clifford Suhyun Cho, Ahmed I. Salem, Robert C. G. Martin et al. "Treatment of borderline resectable (BR) and locally advanced (LA) pancreatic cancer in the era of FOLFIRINOX and gemcitabine plus nab-paclitaxel: A multi-institutional study." Journal of Clinical Oncology 34, n. 4_suppl (1 febbraio 2016): 451. http://dx.doi.org/10.1200/jco.2016.34.4_suppl.451.

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451 Background: FOLFIRINOX or Gemcitabine+nab-Paclitaxel (Gem/nPac) has superior overall survival (OS) compared with gemcitabine alone in pts with Stage 4 pancreatic cancer (PC). Based on these results, FOLFIRINOX or Gem/nPac has been utilized in neoadjuvant (NA) setting for BR and LA PC. This report describes our multi-institutional experience with NA treatment with FOLFIRINOX or Gem/nPac followed by surgical resection. Methods: Pts with BR and LA PC who received NA FOLFIRINOX or Gem/nPac and underwent surgical resection between 2011 and 2015 at 7 high volume pancreas centers were reviewed. Pre-operative chemoradiation therapy (pCXRT) was administered selectively based on radiographic response (RR). Near-complete (minimal residual disease) or complete pathologic response (PR) was categorized as marked PR. Results: 86 pts received either NA FOLFIRINOX (69%) or Gem/nPac therapy (31%) for BR (67%), LA (32%) PC. pCXRT was administered in 71% of pts. Pts received a median of 4 cycles of FOLFIRINOX (range 1-28) and 3 cycles of Gem/nPac (range 2-13). No grade 4-5 toxicities were noted. The majority of pts underwent pancreaticoduodenectomy (84%) and vascular resection was performed in 53% - 40 with venous resection and 6 with arterial resection. R0 resection rate was 86% with no difference between two treatment groups (p = 0.9). Reduction in CA 19-9 or RR did not correlate with pathological response (p = 0.8). A marked PR was seen in 12 pts – 13.6% vs. 15.4% for FOLFIRINOX and Gem/nPac, respectively (p = 0.8). Adjuvant chemotherapy or CXRT was administered in 44% of pts. With a median follow up of 20 months (mo), OS was 27.4 mo with median OS in marked PR was 53 vs. 25 mo in moderate PR/non-responders (p = 0.04). Recurrence was noted in 45 pts – 49% had distant recurrence, 20% had local recurrence and 31% had both. Conclusions: Neoadjuvant FOLFIRINOX or Gem/nPac therapy in conjunction with aggressive surgical resection in BR and select LA PDAC pts result in significant long-term survival especially in marked pathologic responders. Further, optimization of treatment protocols in the neoadjuvant and adjuvant setting is warranted since recurrence rates are high.

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Borghaei, H., M. Smith, M. Millenson, K. Krieger, A. Rogatko e R. Schilder. "Phase I trial of combination therapy with 90Y ibritumomab tiuxetan and gemcitabine in patients with non-Hodgkin’s lymphoma". Journal of Clinical Oncology 24, n. 18_suppl (20 giugno 2006): 17514. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.17514.

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17514 Background: Zevalin (Z) is an effective therapy in patients with relapsed or refractory low grade, follicular, or transformed B-cell non-Hodgkin’s lymphoma (NHL). Gemcitabine (gem) also is active against NHL and is a potent radiation sensitizer. We are conducting a phase I trial to assess the safety of concomitant administration of Z and gem in patients with NHL. Methods: The starting gem dose is 250 mg/m2 on days 1 and 8. Nine patients in three cohorts will be treated with 250 mg/m2 of gem with 0.2, 0.3 or 0.4 mCi/kg of Z. The next cohort can accrue after all patients in the prior cohort have hematologic toxicity has recovered to grade 2 or after 60 days from the date of the last treated patient in the previous cohort. Once it is confirmed that a Z dose of 0.4 mg/kg can be safely administered with gem 250 mg/m2, gem will be escalated according to a Bayesian based system. Response evaluation is based on the International Workshop on Standardized Response Criteria for Non-Hodgkin’s lymphomas. Eligibility criteria include: any histology of recurrent NHL (not candidates for high dose therapy), platelets ≥ 150,000/ul; < 25% bone marrow involvement by lymphoma; prior radiation to < 25% radiation of bone marrow and no prior bone marrow or stem cell transplant. Results: Five patients have been treated thus far, two with follicular NHL (FL) and three with diffuse large B cell (DLBCL). Median age is 75 (range 55–82). The median number of prior treatments is 2 (range 1–6). One patient with DLBCL is not evaluable. The first three patients received 0.2 mCi/kg and next two patients 0.3 mCi/kg of Zevalin. Toxicity consists of grades 2 & 3 myelosuppression in the first 3 weeks in 3 pts. due to gem and then of grade 2 in 1 pt. at 6 to 8 weeks as is usually seen with Z. One grade 3 leukopenia and one grade 2 thrombocytopenia have been observed resolving within one week. One grade 3 infection occurred, unrelated to the protocol or the study drugs. No grade 3 or 4 non-hematologic toxicity has been seen. In follow up, two patients with FL and one with DLBCL achieved CRu. One patient with DLBCL has progressed and one is not yet evaluable. Conclusions: Our preliminary findings suggest that Z can be safely combined with gem 250 mg/m2 in the treatment of patients with NHL. Dose escalation to full dose Zevalin and then of gemcitabine is continuing. [Table: see text]

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Nakai, Yousuke, Hiroyuki Isayama, Takashi Sasaki, Kei Saito, Naminatsu Takahara, Suguru Mizuno, Tsuyoshi Hamada et al. "A phase 1 trial of GSL (gemcitabine, S-1, LV) combination therapy in advanced pancreatic cancer." Journal of Clinical Oncology 32, n. 3_suppl (20 gennaio 2014): 290. http://dx.doi.org/10.1200/jco.2014.32.3_suppl.290.

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Abstract (sommario):

290 Background: Our previous randomized controlled trial, GEMSAP study (Br J Cancer. 2012 5;106:1934-9), showed a combination therapy of gemcitabine (Gem) & S-1 (GS) for advanced pancreatic cancer was superior to Gem monotherapy in terms of progression-free survival (PFS) but not overall survival (OS). Leucovorin (LV) is known to enhance efficacy of S-1 and we conducted this phase 1 trial of combination therapy of Gem, S-1 and LV (GSL). Methods: A primary endpoint of this classical “3+3” design phase 1 trial is to determine recommended dose of GSL. Inclusion criteria were 1. histologically-confirmed advanced pancreatic cancer without prior treatment, 2.PS 0-2, 3. age over 20. Treatment schedule was S-1 80 mg/m2 2x p.o. days 1-7, LV50mg 2x p.o. days 1-7, Gem 600(Level1), 800(Level2), 1000 mg/m2(Level3) div 30-min day 1 in a 2-week schedule. Dose-limiting toxicities were Grade 4 hematological and Grade ≥3 non-hematological toxicities, or delay of recovery from treatment-related toxicity for more than 2 weeks. Results: Between May 2012 and Feb 2013, 15 patients (Level 1/2/3: 6/6/3 patients) were enrolled; 7 males, a median age of 66, PS 0/1: 5/10, locally advanced/metastatic: 5/10. DLT was observed in 2/6 in Level 1 (Grade 3 anorexia in 1 and Grade 3 anorexia/stomatitis/diarrhea in 1) and 1/6 in Level 2 (Grade 3 pulmonary embolism). No DLT was observed in Level 3 and RD was determined as 1,000 mg/m2of Gem. Tumor response by RECIST was PR 5, SD 9, NE 1 with response rate of 33% and disease control rate of 93%. Overall toxicities greater than 3 were neutropenia 20%, anemia 7%, anorexia 13%, diarrhea 7%, stomatitis 7% and pneumonitis 7%. Conclusions: RD of GSL was determined as GEM 1000 mg/m2 div 30 min day 1, S-1 80 mg/m2 2x, LV50mg 2x p.o. days 1-7. GSL was tolerable and showed promising tumor response in advanced pancreatic cancer. Clinical trial information: UMIN000007556.

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Postlewait, Lauren McLendon, Cecilia G. Ethun, David A. Kooby, Juan Sarmiento, Charles A. Staley, Edith Brutcher, Volkan Adsay, Bassel F. El-Rayes e Shishir Kumar Maithel. "A molecular biomarker targeted approach to adjuvant therapy for resected pancreatic adenocarcinoma: Results of a phase II prospective trial." Journal of Clinical Oncology 34, n. 4_suppl (1 febbraio 2016): 230. http://dx.doi.org/10.1200/jco.2016.34.4_suppl.230.

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230 Background: Standard adjuvant treatment for resected pancreatic adenocarcinoma is gemcitabine (Gem) (CONKO-001 trial: Gem vs placebo DFS 13.4 vs 6.7 mo; p<0.001; OS 22.8 vs 20.2 mo; p=0.01). Adding cisplatin (Cis) to Gem has shown increased response rates in the metastatic setting. This benefit may be inhibited by high expression of excision repair cross-complementing gene–1 (ERCC1), the key enzyme in nucleotide excision repair. This Phase II prospective trial assesses outcomes of patients treated with adjuvant Gem/Cis chemotherapy, stratifying results by tumor ERCC1 expression. Methods: Patients with resected pancreatic adenocarcinoma at a single institution were enrolled from 2010-2013. Initially, patients received Gem (1000 mg/m2) / Cis (50 mg/m2) Day 1/8/15, Q28d for 6 cycles. After enrolling 5 pts, this was modified to Day 1/15 due to toxicity. Two dose reductions were permitted. Intent to treat analyses were conducted. Tumor ERCC1 expression was evaluated by immunohistochemistry and dichotomized into low and high expression groups. Primary outcomes were RFS and OS stratified by ERCC1 expression. Results: Of 22 pts, 16 (73%) had Stage IIB disease, 5 (23%) Stage IIA, and 1 (4%) Stage IA. Thirteen (59%) completed all 6 cycles of therapy, of whom 9 required dose reduction. Of the remaining 9 pts, 4 completed >68% of intended therapy. Grade 3 and 4 toxicity occurred in 13 pts (59%); neutropenia was most common (n=9;41%). Median follow-up was 37.5 mo. Median RFS was 16.7 mo, and OS was 35.5 mo. ERCC1 tumor expression data were available for 20 pts: 15 low (75%) and 5 high (25%). Low compared to high ERCC1 was not associated with improved RFS (12.4 vs 16.7 mo; p=0.68) or OS (Median not reached vs 21.6 mo; p=0.22). Conclusions: Adjuvant gemcitabine/cisplatin is tolerated by patients with resected pancreatic adenocarcinoma. RFS and OS for Gem/Cis appear promising compared to historic control. Tumor ERCC1 expression can be reliably evaluated, and low expression is present in the majority of patients. Further prospective trials evaluating Gem/Cis as an adjuvant regimen and ERCC-1 as a biomarker in resected pancreatic adenocarcinoma are warranted. Clinical trial information: NCT01188109.

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Lee, Seung-Hwan, U.-Syn Ha, Sung-Hoo Hong, Ji Youl Lee e In-Ho Kim. "Clinical impact of gemcitabine mono-maintenance versus best supportive care after first-line gemcitabine with platinum in patients with metastatic urothelial carcinoma." Journal of Clinical Oncology 37, n. 7_suppl (1 marzo 2019): 404. http://dx.doi.org/10.1200/jco.2019.37.7_suppl.404.

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Abstract (sommario):

404 Background: To evaluate the clinical impact of gemcitabine (GEM) monotherapy after 1st line GEM with platinum in patients with metastatic urothelial carcinoma. Methods: We retrospectively reviewed the medical records of 113 patients who showed with radiological response or stabilization after 4-6 cycles of GEM with platinum.61 patients received maintenance of GEM-mono (GEM group) as 1000 mg/m2 on day 1 and 8 every three weeks until progression or development of unacceptable toxicity. And 52 patients received best supportive care (BSC) with regular radiologic evaluation (BSC group). Progression free survival (PFS) and overall survival (OS) from start date of GEM-mono or BSC was examined. Results: After a median follow-up of all population of 8.21 months, 43 (70%) patients had progressed and 32 (52%) died in the GEM-mono arm, compared to 45 (86%) and 39 (76%) in the BSC arm, respectively. Maintenance of GEM-mono was for a median 6 cycles (2-19). Median PFS was 7–12 months (range 1.5-13.0) in the GEM-mono arm and 4–8 months (range 1.4-8.6) in the BSC arm (Hazard Ratio 0.580, 95%CI 0.38-0.95, p=0.032). Most common grade 3/4 adverse events in the GEM arm were neutropenia (n=11; 18%) and fatigue (n=13; 21%). After progression, 42 (68%) patients received treatment at the GEM and 30 (58%) at the BSC arm. Conclusions: Our data suggest that maintenance of GEM-mono therapy in patients who responded to 1st line GEM with platinum provides a significant prolongation of PFS, and with a manageable toxicity profile.

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Loehr, M., G. Bodoky, U. Fölsch, A. Märten, M. Karrasch, C. Lilla, I. Meyer, D. Osinsky, J. Szanto e M. Lutz. "Cationic liposomal paclitaxel in combination with gemcitabine in patients with advanced pancreatic cancer: A phase II trial". Journal of Clinical Oncology 27, n. 15_suppl (20 maggio 2009): 4526. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.4526.

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4526 Background: EndoTAG-1 is a novel cationic liposomal formulation of paclitaxel being developed for the treatment of solid malignancies. It acts by targeting activated negatively charged endothelial cells of tumor blood vessels. We present safety and efficacy data of a randomized, controlled phase II trial in pancreatic cancer (PC). Methods: 200 patients with advanced PC were randomized to 1st line treatment with weekly gemcitabine (GEM: 1000 mg/m2) and twice weekly infusions of EndoTAG-1 (E) at 3 different dose levels (Elow: 11 mg/m2, Emed: 22 mg/m2, Ehigh: 44 mg/m2) or GEM monotherapy. Patients were treated for 7 weeks and followed up for overall survival (OS) for at least 1 year. After finishing study treatment, any anti-tumor therapy was allowed. A subgroup of patients had the option to receive repeated cycles of combination therapy in case of at least stable disease according to RECIST until disease progression. Results: Median OS was substantially higher in the GEM+Emed and GEM+ Ehigh groups than the GEM monotherapy group. Adjusted hazard ratios for OS were 0.72 (95% CI 0.46–1.13) and 0.67 (0.43–1.07). In patients receiving >1 treatment cycle, median OS was 11.5 months (GEM+Ehigh); in the GEM+Emed group 75% of patients were alive at 1 year. Treatment with EndoTAG-1 and gemcitabine was generally well tolerated. A trend for increasing adverse event frequency with EndoTAG-1 dose was observed for infusion-related reactions associated with chills and pyrexia, and thrombocytopenia. The overall frequency of serious adverse events in the GEM+E groups was low, the most frequent SAE being pyrexia in 4 (8%) patients in the GEM+Ehigh group. There was no indication for significant organ toxicity associated with EndoTAG-1, even in patients receiving multiple treatment cycles. Conclusions: This phase II trial indicates a considerable survival benefit for patients with advanced PC receiving EndoTAG-1 in combination with gemcitabine and a favourable safety profile warranting further development of EndoTAG-1 in this indication. [Table: see text]

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Tehfe, Mustapha Ali, Scot D. Dowden, Hagen F. Kennecke, Robert Hassan El-Maraghi, Bernard Lesperance, Felix Couture, Richard Letourneau, Darryl Neil Penenberg, Alfredo Romano e Daniel D. Von Hoff. "Phase III study of nab-paclitaxel (nab-P) plus gemcitabine (Gem) versus Gem alone in patients (pts) with metastatic pancreatic adenocarcinoma (mPC): Subgroup analysis of Canadian pts from the MPACT trial." Journal of Clinical Oncology 33, n. 3_suppl (20 gennaio 2015): 439. http://dx.doi.org/10.1200/jco.2015.33.3_suppl.439.

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439 Background: Weekly nab-P + Gem is a new option for first-line treatment (Tx) of mPC. In the MPACT trial, nab-P/Gem demonstrated superior overall survival (OS; primary endpoint) vs Gem alone as first-line Tx of mPC (Table). Here we report a subgroup analyses evaluating the efficacy and safety outcomes with nab-P + Gem vs Gem alone from the Canadian cohort of the MPACT trial. Methods: Previously untreated pts (N = 861) with mPC were randomized 1:1 (stratified by Karnofsky Performance Status [KPS], region, and the presence of liver metastases) to receive nab-P 125 mg/m2 + Gem 1000 mg/m2 on days 1, 8, and 15 of each 28-day cycle or Gem 1000 mg/m2 weekly for 7 weeks followed by 1 week of rest (cycle 1) and then days 1, 8, and 15 of each 28-day cycle (cycle ≥ 2). Results: 63 pts from Canada enrolled in the MPACT trial. Baseline pt characteristics were well balanced. Median age was 61 years and KPS was similar for both groups and comparable to the intent-to-treat (ITT) populations. Primary lesion in the pancreatic head was more common among pts in the nab-P + Gem vs Gem arm (55% vs 30%); use of biliary stent was similar (33% nab-P + Gem; 27% Gem). Median OS and progression-free survival (PFS) were longer with nab-P + Gem vs Gem (Table). Median Tx duration was 4.2 mo with nab-P + Gem vs 3.2 mo with Gem. Use of subsequent therapy was 30% in the nab-P + Gem arm vs 43% in the Gem arm. The median relative dose intensity for Gem was similar in each arm (81% nab-P + Gem vs 85% Gem). The most common grade ≥ 3 AEs for nab-P + Gem vs Gem were neutropenia (22% vs 10%), fatigue (34% vs 33%), and neuropathy (25% vs 0%). Conclusions: Canadian pts participating in MPACT were similar to the ITT population and nab-P + Gem was well tolerated and showed improved median OS, PFS, and ORR vs Gem alone, although not statistically significant (likely due to the small number of pts). Clinical trial information: NCT00844649. [Table: see text]

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Desai, S. P., E. Ben-Josef, T. J. Lawrence, I. R. Francis, J. K. Greenson, C. E. Alfred, L. M. Colletti, D. M. Simeone, D. P. Normolle e M. M. Zalupski. "A phase I study of oxaliplatin, full-dose gemcitabine and concurrent radiation therapy in patients with pancreatic cancer". Journal of Clinical Oncology 24, n. 18_suppl (20 giugno 2006): 4107. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.4107.

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4107 Background: We previously demonstrated safety and efficacy of full dose gemcitabine (GEM) and radiation therapy (RT) in patients (pts) with pancreatic cancer (PC). Our preclinical studies have shown that GEM with oxaliplatin (OX) preserves radiosensitization with synergistic cytotoxicity. To enhance local and systemic treatment effects, we initiated a study of OX and GEM with concurrent RT. Methods: Pts with untreated PC received up to 4 cycles of GEM day 1, 8, 15 and OX days 1, 15 repeated at 28 day intervals. RT (27 Gy in 1.8 Gy fractions to gross tumor volume with 1 cm margin) was given during cycle 1 and repeated in cycle 4. Surgery occurred after cycle 2 in resectable pts. Dose escalation was guided using time-to-event continuous reassessment method (TITE-CRM). Dose levels 1–4 GEM 1 g/m2 IV over 30 min and OX 40, 55, 70, 85 mg/m2 IV over 90 min; dose level 5, 6 OX dose remained 85 mg/m2 but infusion time for GEM 1 g/m2 was increased to 65, 100 min, respectively. Trial objective is to determine dose level associated with DLT thru cycle 2 in ≤ 20% of pts; planned accrual is 40 pts evaluable for DLT. Results: 40 pts have been enrolled (median age 63, men/women 26/14) with resectable (10), unresectable (27), and metastatic (3) PC. 29 pts have completed 2 cycles and 11 pts 4 cycles. After 2 cycles CA19–9 decreased > 50% in 14 of 24 evaluable pts (58%). Six of 8 explored pts underwent margin negative resection with 1 path CR and 2 with small residual microscopic foci only. Per RECIST, CT response of the primary lesion after 2 cycles included 3 PR, 23 SD and 1 PD. Two additional PR were seen after cycle 4. Thirty pts are presently evaluable for DLT; 7 pts have suffered DLT including grade 4 platelets (4), decline in PS (2), GI bleed (1) and grade 3 weight loss (1). Current estimated probability of DLT is 21% (95% CI 11%,34%) for dose level 3 and 24% (95% CI 13%,37%) for dose level 4. Conclusions: The addition of OX 70–85 mg/m2 days 1, 15 to full dose GEM based RT is tolerable and efficacious. A neoadjuvant phase II study in resectable PC using the MTD defined in this phase I study is planned. Supported by Sanofi-Aventis. [Table: see text]

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Toh, U., T. Fujii, S. Takamori, M. Fukunaga, E. Ogo, N. Seki, H. Yamana e K. Shirouzu. "Combination of gemcitabine and adoptive cell therapy of autologous anti-tumor CTL induces clinical activities in patients with refractory lung cancer". Journal of Clinical Oncology 25, n. 18_suppl (20 giugno 2007): 3053. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.3053.

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3053 Background: Cytotoxic T cells selectively kill autologous tumor cells is powerful for adoptive cell therapy of cancer. Gemcitabine (GEM) is able to induce molecular changes in cancer cells that make them to induce an antigen specific CTL response. This study was to evaluate the anti-tumor and the immunological activity using the CTL in combination with GEM. Methods: The 50Gy irradiated autologous tumor cells were cocultured with PBMCs and CTLs was developed with RPMI 1640 and rIL-2 (50 u/ml) for 7–14 days. Nine pts with non small cell lung cancer failed their prior chemotherapy were enrolled this pilot study. GEM regimen [intravenous (iv.) GEM (1000mg/m2) - day 1, 8 and 15 ] was started without CTL administration for 1st cycle. GEM was administered at least 2 cycles with a 1-week interval and combined with iv. CTL therapy (0.9 x 108 - 4.6 x 108 cells/injection + IL-2 0.4 MIU; biweekly for 6 to 12 injections) from 2nd cycle. The mean total administered T cells were reached to 3.9 x 109 - 5.6 x 109. PBMCs were analyzed their surface markers by Flow Cytometry and the cytokine productions of IFN-γ etc. in the serum were measured by ELISA before and after 1st cycle of GEM administration and 3rd cycles of CTL injection. Results: After finishing 2 cycles of GEM and 3 injections of CTL, the ratio of CD4/CD8 in PBMCs increased in 7/9 pts. In contrast, CD3/CD19 decreased in 6/9 pts. The cytokine production of IFN-γ in the serum revealed an increase after treatment, the levels of TGF-β were decreased simultaneously. There was no remarkable change in the levels of NKG2D in the PBMCs and MIG, IP10 in the serum. The clinical response showed PR/SD/PD was 2/5/2. The tumor marker proteins (CEA) were also decreased significantly in 4 of 9 pts. The adverse effects were tolerable with grade <2 fever, nausea and fatigue and no bone marrow suppression was observed. Conclusions: These results suggested the synergistic enhancement of antitumor effect might be induced between CTLs and anti-cancer agent GEM. Marked clinical responses were observed in two pts after the treatment. Thus this chemo-immunotherapy will be applicable for the patients with refractory lung cancer. No significant financial relationships to disclose.

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Betge, Johannes, Nicolai Haertel, Jing Chi-Kern, Sebastian Belle, Nadine Schulte, Martin Maenz, Ulrich Wedding e Matthias Philip Ebert. "A multicenter phase 4 geriatric assessment directed trial to evaluate gemcitabine +/- nab-paclitaxel in elderly pancreatic cancer patients (GrantPax)." Journal of Clinical Oncology 35, n. 15_suppl (20 maggio 2017): TPS10124. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.tps10124.

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TPS10124 Background: Nab-paclitaxel/gemcitabine ( nab-P/gem) is an effective 1st line regimen for metastatic pancreatic ductal adenocarcinoma (mPDAC). Elderly mPDAC patients (pts) may as well benefit from nab-P/gem. Geriatric assessments to evaluate the functional reserve of these pts may allow individualization of treatment. Therefore, the aim of this study is to determine whether comprehensive geriatric assessments (CGAs) can predict the benefit from combined nab-P/gem therapy for elderly mPDAC pts in 1st line. A stratified treatment approach shall result in patient groups with a stable or improving CGA performance during the 1st cycle of treatment. Methods: GrantPax (NCT02812992) is a multicenter, open label phase 4 interventional trial with stratified parallel treatment groups (n = 45 per arm). The hypothesis is that individualized assessment directed treatment algorithms identify elderly pts (≥70 yrs), who benefit from combined nab-P/gem therapy. The study uses a CGA to stratify pts as GOGO, SLOWGO or FRAIL. Depending on test outcome, pts receive chemotherapy (GOGO: nab-P/gem; SLOWGO: gem mono) or best supportive care (FRAIL). After 1st cycle of chemotherapy (4 wks) a CGA and safety assessment will be performed to assign pts to their definite treatment arm. The primary objective is that CGA-stratified pts do not decline in their CGA performance in response to chemotherapy, measured as a loss of 5 points or less in Barthels activities of daily living (ADL1 vs. ADL2 during CGA core assessment). The expected proportion of pts with ADL decline in each treatment group is 6%. Under this assumption it shall be shown with 80% power at one-sided significance level alpha of 0.05 that the proportion of pts with functional decline is less than 20% (n = 43 per group; ADL decline: n = 2 per group). Secondary endpoints are CGA scores during the course of therapy (CGA1-4), response rates, safety, survival rates, duration of treatment, cumulative dose, quality of life and discrepancy between CGA strata estimation by the investigator and true CGA assessment. GrantPax is the first trial realizing a CGA-driven treatment to individualize cancer therapy for elderly pts. Clinical trial information: NCT02812992.

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Awasthi, Niranjan, Katherine T. Ostapoff, Changhua Zhang, Margaret A. Schwarz e Roderich Schwarz. "Comparative benefits of nab-paclitaxel over gemcitabine or polysorbate-based docetaxel in experimental pancreatic cancer." Journal of Clinical Oncology 31, n. 4_suppl (1 febbraio 2013): 192. http://dx.doi.org/10.1200/jco.2013.31.4_suppl.192.

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192 Background: Gemcitabine (Gem), a standard cytotoxic therapy for pancreatic cancer, has shown limited clinical benefits. Nanoparticle albumin-bound (nab) paclitaxel (NPT), an approved treatment for breast cancer, has shown efficacy as mono- and combination therapy in multiple tumor types including pancreatic, lung and ovarian cancer. We evaluated the NPT treatment benefits compared with Gem or solvent-based taxane docetaxel (DT) in experimental pancreatic cancer. Methods: In vitro cell proliferation and protein expression were measured by WST-1 assay and immunoblotting. Tumor growth and animal survival studies were performed in murine xenografts. Intratumoral proliferative activity was measured using Ki67 nuclear antigen staining. Results: For AsPC-1, BxPC-3, MIA PaCa-2 and Panc-1 cells in vitro, Gem IC50 levels were 23.9 mM, 506 nM, 332 nM and 14.5 nM; DT IC50 levels were 30 nM, 4.6 nM, 37.5 nM and 27 nM; and NPT IC50 levels were 7.6 mM, 208 nM, 519 nM and 526 nM. NPT addition decreased Gem IC50 to 1.7 mM, 189 nM, 123 nM and 913 nM; DT addition decreased Gem IC50 to 436 nM, 470 nM, 124 nM and 0.2 nM in AsPC-1, BxPC-3, MIA PaCa-2 and Panc-1 cells, respectively. NPT and DT treatment increased stathmin phosphorylation and decreased tubulin expression in vitro. In a heterotopic in vivo model, net tumor growth inhibition after Gem, DT and NPT was 67, 31 and 72 percent, while intratumoral proliferative index inhibition was 41, 53 and 68 percent, respectively. In an intraperitoneal model, median animal survival was significantly longer in the NPT treatment group (41 days, p<0.002 vs. control and Gem) compared to Gem (32 days, p=0.005 vs. control), DT (32 days, p=0.005 vs. control) and controls (20 days). Animal survival in NPT-Gem and DT-Gem sequential treatment groups was 43 and 40 days, and thus not superior to NPT alone. Conclusions: Nab-paclitaxel has significantly superior antitumor activity as a single agent in experimental pancreatic cancer compared with gemcitabine or docetaxel. These findings provide a strong rationale for considering nab-paclitaxel as first-line monotherapy in patients with pancreatic cancer.

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Costello, Brian Addis, Yingwei Qi, Mitesh J. Borad, George P. Kim, Donald W. Northfelt, Charles Erlichman e Steven R. Alberts. "Phase I trial of everolimus, gemcitabine and cisplatin for patients with solid tumors refractory to standard therapy." Journal of Clinical Oncology 30, n. 15_suppl (20 maggio 2012): e13052-e13052. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e13052.

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e13052 Background: The combination of GEM and CDDP has shown activity in a variety of cancers, including biliary tract/gallbladder. Preclinical testing shows a potential benefit to the addition of EV. Methods: Using a standard 3+3 design, the MTDs of GEM + EV (Cohort I) and GEM + CDDP + EV (Cohort II) were determined as shown in the table. The MTD was defined as the dose level below the lowest dose that induces a DLT in at least one-third of pts. At the MTD of Cohort II, 10 patients were enrolled with biliary tract/gallbladder cancer (Cohort III). A weekly CBC was obtained. Assessments occurred every 3 weeks and imaging for response at every other cycle. Results: In Cohort I (N=12), no DLT occurred at dose level 0, and in dose level 1, grade 3 thrombocytopenia was found in 2 of 6 pts. The MTD for Cohort I was determined to be dose level 0. Responses were seen in 3 pts: 2 CRs (primary peritoneal, pancreatic) and 1 PR (breast). In Cohort II (N=15) DLTs at dose level 0 were neutropenia and thrombocytopenia in 2 of 3 pts and at dose level -1, thrombocytopenia in 2 of 6 pts. At dose level -2, 1 of 6 pts experienced a DLT (grade 3 thrombocytopenia), establishing this dose level as the MTD. Responses were seen in 2 pts, both PRs (ampullary, pheochromocytoma). All 10 pts have been enrolled in Cohort III with 2 DLTs (neutropenia and thrombocytopenia). Stable disease seen in 5 of 7 evaluable pts. Conclusions: Gem + EV was well tolerated at dose level 0, though dose escalation was limited by thrombocytopenia. GEM + CDDP + EV had DLTs of neutropenia and thrombocytopenia leading to the MTD of dose level of -2. Cohort III is fully accrued and the 2 DLTs are hematologic. [Table: see text]

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Choi, Minsig, Sayaka Ishizawa, Yan Liang, Sina Rashidian, Aaron R. Sasson e Eugene Feinberg. "Comparison of neoadjuvant and adjuvant therapy for resectable pancreatic cancer using Markov decision modeling." Journal of Clinical Oncology 37, n. 4_suppl (1 febbraio 2019): 448. http://dx.doi.org/10.1200/jco.2019.37.4_suppl.448.

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

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Rodríguez-Nogales, Carlos, Haritz Moreno, Carolina Zandueta, Didier Desmaële, Fernando Lecanda, Patrick Couvreur e María J. Blanco-Prieto. "Combinatorial Nanomedicine Made of Squalenoyl-Gemcitabine and Edelfosine for the Treatment of Osteosarcoma". Cancers 12, n. 7 (14 luglio 2020): 1895. http://dx.doi.org/10.3390/cancers12071895.

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Due to chemoresistance and a high propensity to form lung metastasis, survival rates in pediatric osteosarcoma (OS) are poor. With the aim to improve anticancer activity in pediatric OS, a multidrug nanomedicine was designed using the alkyl-lysophospholipid edelfosine (EF) co-assembled with squalenoyl–gemcitabine (SQ–Gem) to form nanoassemblies (NAs) of 50 nm. SQ–Gem/EF NAs modified the total Gem pool exposure in the blood stream in comparison with SQ–Gem NAs, which correlated with a better tolerability and a lower toxicity profile after multiple intravenous administrations in mice. For in vivo preclinical assessment in an orthotopic OS tumor model, P1.15 OS cells were intratibially injected in athymic nude mice. SQ–Gem/EF NAs considerably decreased the primary tumor growth kinetics and reduced the number of lung metastases. Our findings support the candidature of this anticancer nanomedicine as a potential pediatric OS therapy.

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Tang, Jun, Fushuang Zheng, Jungang Zhao e Jianzhu Zhao. "Self-assembled multifunctional nanotheranostics loading GEM for targeted lung cancer therapy". Materials Science and Engineering: C 112 (luglio 2020): 110786. http://dx.doi.org/10.1016/j.msec.2020.110786.

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