Gemcitabine And Cisplatin Chemotherapy Research Articles

Targeting CD73 limits tumor progression and enhances anti-tumor activity of anti-PD-1 therapy in intrahepatic cholangiocarcinoma

Background & aimsPatients with intrahepatic cholangiocarcinoma (iCCA) respond poorly to immune checkpoint blockades (ICBs). In this study, we aimed to dissect the potential mechanisms underlying poor response to ICBs and explore a rational ICB-based combination therapy in iCCA.MethodsscRNA-seq dataset GSE151530 was analyzed to investigate the differentially expressed genes in malignant cells following ICBs therapy. RNA-seq analysis and western blot assays were performed to examine the upstream and downstream signaling pathways of CD73. Subcutaneous tumor xenograft models were utilized to investigate the impact of CD73 on iCCA growth. Plasmid AKT/NICD-induced spontaneous murine iCCAs were used to explore the therapeutic efficacy of CD73 enzymatic inhibitor AB680 combined with PD-1 blockade. Time-of-flight mass cytometry (CyTOF) was conducted to identify the tumor-infiltrating immune cell populations and their functional changes in murine iCCAs treated with AB680 in combination with PD-1 antibody.ResultsscRNA-seq analysis identified elevated CD73 expression in malignant cells in response to ICBs therapy. Mechanistically, ICBs therapy upregulated CD73 expression in malignant cells via TNF-α/NF-κB signaling pathway. In vivo studies revealed that CD73 inhibition suppressed the growth of subcutaneous tumors, and achieved synergistic depression effects with gemcitabine and cisplatin (GC). Adenosine produced by CD73 activates AKT/GSK3β/β-catenin signaling axis in iCCA cells. CD73 inhibitor AB680 potentiates anti-tumor efficacy of PD-1 antibody in murine iCCAs. CyTOF analysis showed that AB680 combined with anti-PD-1 therapy promoted the infiltration of CD8+ T, CD4+ T cells, and NK cells in murine iCCAs, while simultaneously decreased the proportions of macrophages and neutrophils. Moreover, AB680 combined with anti-PD-1 significantly upregulated the expression of Granzyme B, Tbet and co-stimulatory molecule ICOS in infiltrating CD8+ T cells.ConclusionsCD73 inhibitor AB680 limits tumor progression and potentiates therapeutic efficacy of GC chemotherapy or anti-PD-1 treatment in iCCA. AB680 combined with anti-PD-1 therapy effectively elicits anti-tumor immune response.

A phase 2, open-label, safety and efficacy study of telotristat ethyl plus first-line chemotherapy in patients with advanced biliary tract cancer.

472 Background: Patients (pts) with unresectable biliary tract cancer (BTC) have a poor prognosis. In preclinical models of cholangiocarcinoma (CCA) telotristat ethyl (TE), a tryptophan hydroxylase inhibitor that reduces production of serotonin, enhanced the antiproliferative effects of gemcitabine and cisplatin (GC) chemotherapy. This trial assessed the safety and efficacy of adding TE to GC chemotherapy in pts with advanced BTC. Methods: This was a Phase 2 open-label study. Eligible pts had unresectable, locally advanced, or metastatic BTC, were treatment naïve and had plans to initiate GC chemotherapy. On Day 1, pts received Gem 1000mg/m2 and Cis 25mg/m2 with TE 250 mg orally three times daily (TID) for 7 days. Thereafter, pts received TE 500 mg TID continuously plus GC therapy on days 1 and 8 of each 21-day cycle. The study comprised of 2 stages: stage 1 would enroll 20 patients with a safety run-in cohort in the first 6 pts to monitor safety and tolerability of TE + GC treatment for 21 days. Stage 2 would enroll 33 patients if no significant/unresolved grade 3 or higher toxicities related to study drug occurred in stage 1. The primary endpoint was 6-month (mo) progression free survival (PFS) rate according to RECIST 1.1. If 60% of pts (≥34) in the safety population were alive and progression free at 6-mos, the study was considered successful. Secondary endpoints included overall response rate (ORR) and disease control rate (DCR). Restaging occurred every 9 weeks using RECIST 1.1 and toxicities were graded using CTCAE v 5.0. Results: Between 2019 and 2021, fifty-three pts were enrolled across 12 study sites and comprised the safety population. The majority of pts were female (62.3%) and median age was 66 yrs (range 33 to 79). Baseline mean plasma 5-HIAA was 11.1 µg/L (ULN defined as >10.8 µg/L). Thirty-one pts (58.5%) had plasma 5-HIAA levels ≤ULN and 22/53 (41.5%) had 5-HIAA levels >ULN. Majority of pts had metastatic BTC (85%) and liver was the most common primary tumor site (66%). The 6-month PFS rate was 22.6% (12/53). Based on blinded independent central review, the ORR was 13.2% and DCR was 62.3%. Mean reduction in plasma 5-HIAA at 6 mos was -1.735 µg/L (SD 8.69) in 24 patients with available data. There was no difference in 6-mo PFS rate based on pts baseline 5-HIAA status; 58% (14/24) pts had ≥30% decrease from baseline in 5-HIAA, however there was no correlation with 6-month PFS. The most common TE related TEAEs were constipation (43.4%), nausea (28.3%) and fatigue (28.3%). Conclusions: The study did not achieve its primary endpoint of 60% of patients on TE plus GC chemotherapy being alive and progression free at 6 months. TE did reduce 5-HIAA levels in a subset of pts; however, this did not correlate to improved clinical outcomes. No significant safety issues noted with TE in combination with GC chemotherapy. Clinical trial information: NCT03790111 .

The addition of tislelizumab to gemcitabine and cisplatin chemotherapy increases thrombocytopenia in patients with urothelial carcinoma: A single-center study based on propensity score matching.

Whether the addition of tislelizumab to gemcitabine and cisplatin (GC) chemotherapy increases the incidence of myelosuppression has not been well established. This study identified the risk factors for the development of myelosuppression in patients with urothelial carcinoma (UC) after receiving GC chemotherapy with or without tislelizumab. We enrolled 192 UC patients who received GC with or without tislelizumab at the Affiliated Hospital of Xuzhou Medical University between July 2014 and November 2022. Patient baseline characteristics were included in the statistical analyses after adjusting for previously reported risk factors affecting survival using propensity score matching (1:1). Binary logistic regression analysis was used to identify the risk factors associated with posttreatment myelosuppression. A total of 192 patients were enrolled, of whom 96 were treated with tislelizumab plus gemcitabine and cisplatin (T + GC) and 96 with GC alone. The incidence of leukopenia, anemia, and thrombocytopenia of any grade was 50.0%, 70.8%, and 42.7%, respectively, in the T + GC group and 41.7%, 72.9%, and 20.8%, respectively, in the GC group. In multivariate analysis, patients aged over 70 years (OR = 2.486, 95% CI: 1.067-5.792, p = 0.035) and those who received T + GC (OR = 3.119, 95% CI: 1.576-6.173, p = 0.001) were more likely to develop thrombocytopenia. Patients aged over 70 years (OR = 3.213, 95% CI: 1.254-8.237, p = 0.015) were more likely to develop anemia, and patients with renal insufficiency (OR = 2.105, 95% CI: 1.035-4.280, p = 0.040) were more likely to develop leukopenia. Eventually, 99 (51.6%) patients with UC successfully completed all the treatment cycles. This study demonstrates that the addition of tislelizumab to GC chemotherapy led to a considerable increase in the occurrence of thrombocytopenia, whereas no significant changes were observed regarding anemia or leukopenia. It is crucial to fully inform patients at increased risk for myelosuppression of potential risks and closely monitor changes in their blood routines.

Tislelizumab (Tisle) combined with/without gemcitabine and cisplatin (GC) as adjuvant therapy in patients at high risk after upper urothelial carcinoma (UTUC) surgery: A real-world study.

e16592 Background: In China, UTUC affects 9.3% - 19.9% of urothelial carcinoma(UC) patients(Pts), comparing to 5%-10% in western countries. Radical nephroureterectomy (RNU) is the standard of care for locally advanced UTUC; however, patient prognosis remains suboptimal, and previous studies have shown a controversial survival benefit of postoperative adjuvant chemotherapy in pts with UTUC. Immune checkpoint inhibitors(ICI) have been demonstrated to improve disease-free survival (DFS) in pts after adjuvant therapy for UC, but the data from UTUC studies is limited. This study is intended to evaluate real-world study data on whether Tisle with/without GC is able to achieve better survival benefit in pts with UTUC. Methods: UTUC pts with clinical diagnosis of T1N1 or T2-T4aN0-1M0, ECOG ps of 0-1, could tolerate surgery and had adequate renal functional reserve after surgery. Enrolled pts underwent RNU surgery and adjuvant therapy was started within 90 days after surgery. ICI: 200 mg in day1(D1), Q3w regimen, when to discontinue the drug was assessed by clinicians, and the reasons for disease progression and intolerable toxicity; GC chemotherapy: gemcitabine 1000 mg/m2 D1, D8, cisplatin 70 mg/m2 D2, up to 6 (0-6) cycles. Primary endpoint: 3-year Overall survival (OS) rate; secondary endpoints included 5-year OS rate, tumor-related survival (CSS) and safety. Results: A total of 60 pts received the above treatment from Jan 2020 to Dec 2022, of whom 5 pts were considered to have metastases at initial diagnosis at further evaluation and were finally evaluated for safety only. Fifty-five pts were evaluable for response, with a median follow-up time of 21.5 (3-33) months, and 70.91% (39/55) of pts were followed up for more than 12 months. The OS rate was 93.14% at 1 year and 76.21% at 2 years. Tisle was administered for a median of 6 (1-14) cycles, with a 7.19% and 24.79% lower risk of death at 1 and 2 years in pts with Tisle ≥ 3 cycles compared with pts with Tisle < 3 cycles (HR: 0.368, 95% CI (0.076-1.781); p = 0.162). GC was administered for a median of 3 (0-6) cycles, with a 3.7% and 24.8% lower risk of death at 1 and 2 years in pts with GC＞2 cycles compared with pts with GC≤2 cycles (HR: 0.218, 95% CI (0.045-0.970); p = 0.110). The incidence of treatment-related adverse reactions (trAEs) of any grade was 91.64%; the incidence of trAEs of grade 3-4 was 18.33%, mainly manifested as leukopenic, gastrointestinal reaction and thrombocytopenia. The incidence of immune-related adverse reactions (irAEs) was 25%, and no irAEs of grade 3 or higher were found. The enrollment and follow-up of the present study are currently ongoing. Conclusions: Encouraging efficacy data and safety have been preliminarily observed with adjuvant Tisle with/without GC chemotherapy in high-risk pts after UTUC surgery. Final results also need to be observed in further studies.

Probiotics enhances anti-tumor immune response induced by gemcitabine plus cisplatin chemotherapy for urothelial cancer.

Chemotherapy drugs, such as gemcitabine and cisplatin (GC), are frequently administered to patients with advanced urothelial carcinoma, however the influence of the gut microbiota on their action is unclear. Thus, we investigated the effects of GC on the gut microbiome and determined whether oral supplementation with a probiotics mixture of Lactobacillus casei Shirota and Bifidobacterium breve enhanced the anti-tumor immune response. After subcutaneous inoculation with MBT2 murine bladder cancer cells, syngenic C3H mice were randomly allocated into eight groups. The gut microbiome cluster pattern was altered in both the GC and oral probiotics groups (p=0.025). Both tumor-bearing conditions (no treatment) and GC chemotherapy influenced Pseudoclostridium, Robinsoniella, Merdimonas, and Phocea in the gut. Furthermore, comparison of the GC-treated and GC + probiotics groups revealed an association of four methyltransferase family enzymes and two short-change fatty acid-related enzymes with oral probiotics use. A significant difference in tumor volume was observed between the GC and GC + probiotics groups at week 2 of treatment. Additionally, decreased recruitment of cancer-associated fibroblasts and regulatory T cells, and activation of CD8+ T cells and dendritic cells were observed in the tumor microenvironment. Our findings reveal the positive effects of a probiotics mixture of Lactobacillus and Bifidobacterium in enhancing anti-tumor effects through the gut-tumor immune response axis. Future clinical trials are needed to evaluate the full benefits of this novel supplement with oral probiotics in patients with advanced urothelial carcinoma.

The immune modulation effects of gemcitabine plus cisplatin induction chemotherapy in nasopharyngeal carcinoma.

BackgroundStudies are trying to add immunotherapy to gemcitabine and cisplatin (GP) induction chemotherapy, the standard therapy, in nasopharyngeal carcinoma (NPC) patients with locoregionally advanced disease. However, how the immune system responds to GP remains unknown.MethodWe examined the dynamic changes of circulating immune cells and plasma cytokines in NPC patients administered with GP.ResultAfter GP administration, immunosuppressive myeloid cells, including CD11b+CD14+ monocytes, CD33+ myeloid cells, CD33+CD11+ myeloid cells, total MDSCs (CD33+CD11+HLA‐DR−/low), monocytic MDSCs, and granulocytic MDSCs decreased significantly. The regulatory T cells and B cells, two important suppressive lymphocyte subpopulations, also decreased. On the other hand, the levels of CD3+ T cells, total B cells, central memory CD4+ T cells, and pro‐inflammatory cytokines (including Interleukin [IL]‐1β, IL‐6, IL‐2, IL‐5, and IL‐8) increased significantly after GP administration. Besides, GP chemotherapy did not weaken the cytotoxic activity and proliferative capacity of T cells.ConclusionOur results showed the immune modulation effect of GP induction chemotherapy in locoregionally advanced NPC, providing a solid basis for its combination with immunotherapy.

Clinical efficacy and safety of Kanglaite injection, adjuvant cemcitabine and cisplatin chemotherapy for advanced non-small-cell lung cancer: A systematic review and meta-analysis

Purpose: To investigate the effectiveness and safety of the combination of Kanglaite injection (KLTi) and gemcitabine and cisplatin (GP) chemotherapy in the treatment of advanced non-small cell lung cancer (NSCLC).Methods: PubMed, Web of Science, Embase, Cochrane Library, CNKI, Wan-Fang, CBM, and CQVIP were comprehensively searched from January 2010 till November 2020. Randomized controlled trials (RCTs) of KLTi plus GP in the treatment of NSCLC were selected and assessed for inclusion. Review Manager 5.3 software was used for meta-analysis.Results: Twenty-five RCTs on advanced NSCLC examined the inclusion criteria. The meta-analysis showed that compared with GP chemotherapy alone, KLTi plus GP chemotherapy significantly improved objective response rate (ORR) (RR = 1.36, 95% CI 1.23-1.51, p < 0.00001), disease control rate (DCR) (RR = 1.17, 95% CI 1.11 - 1.23, p < 0.00001), and reduced adverse drug reactions(ADRs) such as hair loss (RR = 0.60, 95% CI 0.47 - 0.76, p < 0.0001), gastrointestinal reaction (RR = 0.68, 95% CI 0.62 - 0.75, p < 0.00001), impairment of liver and kidney function (RR = 0.65, 95% CI 0.53 - 0.80, p < 0.001), nervous system damage (RR = 0.42, 95% CI 0.26 - 0.69, p = 0.0005), myelosuppression (I-II phase) (RR = 0.79, 95 % CI 0.66 - 0.95, p = 0.01), myelosuppression (III-IV phase) (RR = 0.44, 95 % CI0.27 - 0.72, p = 0.001), anemia (RR = 0.74, 95 % CI 0.60 - 0.91, p = 0.006), leukopenia (RR = 0.78, 95% CI 0.69, 0.87, p < 0.0001), thrombocytopenia (RR = 0.59, 95 % CI 0.49, 0.72, p < 0.00001), hypochromia (RR = 0.74, 95% CI 0.59, 0.92, p = 0.008).Conclusion: KLTi adjuvant GP chemotherapy reduces adverse effects in patients with advanced NSCLC. Thus, KLTi might be an effective and safe intervention for NSCLC

Supplementary Oral Anamorelin Mitigates Anorexia and Skeletal Muscle Atrophy Induced by Gemcitabine Plus Cisplatin Systemic Chemotherapy in a Mouse Model.

Chemotherapy-induced adverse effects can reduce the relative dose intensity and quality of life. In this study, we investigated the potential benefit of supplementary anamorelin and 5-aminolevulinic acid (5-ALA) as preventive interventions against a gemcitabine and cisplatin (GC) combination chemotherapy-induced adverse effects in a mouse model. Non-cancer-bearing C3H mice were randomly allocated as follows and treated for 2 weeks—(1) non-treated control, (2) oral anamorelin alone, (3) oral 5-ALA alone, (4) gemcitabine and cisplatin (GC) chemotherapy, (5) GC plus anamorelin, and (6) GC plus 5-ALA. GC chemotherapy significantly decreased body weight, food intake, skeletal muscle mass and induced severe gastric mucositis, which resulted in decreased ghrelin production and blood ghrelin level. The supplementation of oral anamorelin to GC chemotherapy successfully mitigated decrease of food intake during the treatment period and body weight loss at day 8. In addition, analysis of the resected muscles and stomach revealed that anamorelin suppressed chemotherapy-induced skeletal muscle atrophy by mediating the downregulation of forkhead box protein O-1 (FOXO1)/atrogin-1 signaling and gastric damage. Our findings suggest the preventive effect of anamorelin against GC combination chemotherapy, which was selected for patients with some types of advanced malignancies in clinical practice.

Timing of changing therapy from gemcitabine and cisplatin chemotherapy based on real‑world data of advanced urothelial carcinoma

Cisplatin-based systemic chemotherapy is the gold-standard approach for the first-line treatment of patients with advanced or metastatic urothelial carcinoma (UC). However, the optimal number of cycles is still unclear. The current study retrospectively assessed the clinical outcome in patients who received gemcitabine and cisplatin (GC) chemotherapy as first-line treatment for metastatic urothelial cancer to clarify the timing of switching from GC therapy. A total of 61 patients with locally advanced or metastatic UC who received first-line chemotherapy with GC were retrospectively reviewed at National Hospital Organization Kyushu Cancer Center between June 2009 and August 2017. The progression-free survival (PFS) and overall survival (OS) were evaluated using the Kaplan-Meier method. The significance of associations between the clinical parameters and OS was assessed using the Cox proportional hazards regression model. The median cycle number for GC chemotherapy was 4. The median PFS and OS of all cases was 5.2 and 14.1 months, respectively. The multivariate analyses revealed that a neutrophil-to-lymphocyte ratio ≥3.0 (hazard ratio [HR], 2.521, 95% confidence interval [CI]=1.179–5.624; P=0.017) and best response to GC therapy of CR+PR (HR 0.110; 95% CI=0.028–0.411; P<0.001) were independent prognostic factors. However, the number of GC cycles (≤4 vs. >4) was not an independent prognostic factor (P=0.387). The current retrospective study indicated that changes to therapy should be considered at an early stage for cases with a therapeutic effect of SD or less, regardless of the number of GC therapy cycles.

Supplementary granulocyte macrophage colony-stimulating factor to chemotherapy and programmed death-ligand 1 blockade decreases local recurrence after surgery in bladder cancer.

Despite advances and refinements in surgery and perioperative chemotherapy, there are still unmet medical needs with respect to radical cystectomy for muscle‐invasive bladder cancer (MIBC). We investigated the potential benefit of supplementary granulocyte macrophage colony‐stimulating factor (GM‐CSF) to chemoimmunotherapy with programmed cell death protein‐1 (PD‐1)/programmed death‐ligand 1 (PD‐L1) axis blockade and standard neoadjuvant chemotherapy in bladder cancer. We inoculated 2 × 105 MBT2 cells s.c. in C3H mice to create a syngeneic animal model of local recurrence (LR). When the tumor diameter reached 12 mm, the mice were allocated randomly as follows: (i) non‐treated control (vehicle only); (ii) anti‐mPD‐L1 monotherapy; (iii) mGM‐CSF monotherapy; (iv) anti‐mPD‐L1 plus mGM‐CSF; (v) gemcitabine and cisplatin (GC); (vi) GC plus anti‐mPD‐L1; (vii) GC plus mGM‐CSF; and (viii) GC plus anti‐mPD‐L1 plus mGM‐CSF. After completing 2‐week neoadjuvant therapy, tumors were resected for resection margin evaluation and immunohistochemical staining and blood was collected for flow cytometry and ELISA. Operative wounds were sutured, and the operative site was monitored to detect LR. Addition of anti‐mPD‐L1 and mGM‐CSF to neoadjuvant GC chemotherapy enhanced the antitumor effect and reduced positive resection margins (50% vs 12.5%). Combination of GC, anti‐mPD‐L1, and mGM‐CSF resulted in longer LR‐free survival and cancer‐specific survival compared to those in other groups. These effects involved an immunotherapy‐related decrease in oncological properties such as tumor invasion capacity and epithelial‐mesenchymal transition. mGM‐CSF significantly decreased the accumulation of myeloid‐derived suppressor cells in both the blood and tumor microenvironment and blood interleukin‐6 levels. Supplementary GM‐CSF to neoadjuvant GC plus PD‐L1 blockade could decrease LR after radical surgery by immune modulation in the blood and tumor microenvironment.

Effects of Chemotherapy-Induced Neutropenia on Overall Survival in Patients With Unresectable or Metastatic Urothelial Carcinoma to Gemcitabine Plus Cisplatin Combination Chemotherapy.

Chemotherapy-induced neutropenia (CIN) is an important dose-limiting toxicity of chemotherapy. However, evidence suggests that the occurrence of CIN may be predictive of treatment outcome. Indeed, studies have revealed that the onset of CIN is associated with a good chemotherapeutic response. The purpose of this study was to investigate the association between the onset of CIN and overall survival in patients with unresectable or metastatic urothelial carcinoma (UC) who received a combination regimen of gemcitabine and cisplatin (GC). Medical records from 56 patients with unresectable or metastatic UC who were treated with a combination GC regimen between December 2005 and May 2016 were retrospectively analyzed to investigate the association between CIN development and survival. The median duration of survival was 521 days (95% CI = 147-193 days) for patients with severe CIN and 287 days for patients without CIN. Additional multivariate analysis revealed that both the presence of severe CIN (hazard ratio [HR] = 0.399; 95% CI = 0.180-0.880, P = 0.023) and baseline hemoglobin (HR = 2.167; 95% CI = 1.170-4.014, P = 0.014) represented independent prognostic factors for the survival of patients with unresectable or metastatic UC receiving GC treatment. Conclusion and Relevance: CIN onset was associated with longer survival in patients receiving GC therapy for unresectable or metastatic UC, suggesting that neutropenia monitoring during GC chemotherapy may be predictive of treatment efficacy.

Assessment of Concurrent Chemoradiotherapy plus Induction Chemotherapy in Advanced Nasopharyngeal Carcinoma: Cisplatin, Fluorouracil, and Docetaxel versus Gemcitabine and Cisplatin

Induction chemotherapy treatment for nasopharyngeal carcinoma (NPC) is controversial. The aim of this study was to evaluate the treatment outcomes and toxicities between two induction chemotherapy regimens, with both followed by concurrent chemoradiotherapy. The first strategy used docetaxel, cisplatin and fluorouracil for induction chemotherapy (TPF), and the second utilised gemcitabine and cisplatin (GP). A retrospective analysis was performed on eligible NPC patients attending our hospital between May 2009 and Dec 2014. A total of 113 patients were enrolled with 58 patients receiving TPF and 55 receiving GP induction chemotherapy. Ninety-four patients (83.2%) were alive after 36-months follow-up. The median overall survival (OS) and progression-free survival (PFS) time were 48.3 and 39.7 months, respectively. The 3-year OS for the TPF regimen was 87.9% and 87.4% with GP chemotherapy (P = 0.928). The 3-year PFS of the TPF treatment was 84.5%, while it was 83.5% for the GP group (P = 0.551). Univariate analysis showed that lymph node metastasis was a significant PFS prognostic factor, while N3 stage was an independent predictor of PFS and distant failure-free survival (DMFS) in multivariate analysis. There were no significant differences in adverse toxicities or treatment efficacy between the chemotherapy regimens in the treatment of locoregionally advanced NPC.

SPIRE \u2013 combining SGI-110 with cisplatin and gemcitabine chemotherapy for solid malignancies including bladder cancer: study protocol for a phase Ib/randomised IIa open label clinical trial

BackgroundUrothelial bladder cancer (UBC) accounts for 10,000 new diagnoses and 5000 deaths annually in the UK (Cancer Research UK, http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/bladder-cancer, Cancer Research UK, Accessed 26 Mar 2018). Cisplatin-based chemotherapy is standard of care therapy for UBC for both palliative first-line treatment of advanced/metastatic disease and radical neoadjuvant treatment of localised muscle invasive bladder cancer. However, cisplatin resistance remains a critical cause of treatment failure and a barrier to therapeutic advance in UBC. Based on supportive pre-clinical data, we hypothesised that DNA methyltransferase inhibition would circumvent cisplatin resistance in UBC and potentially other cancers.MethodsThe addition of SGI-110 (guadecitabine, a DNA methyltransferase inhibitor) to conventional doublet therapy of gemcitabine and cisplatin (GC) is being tested within the phase Ib/IIa SPIRE clinical trial. SPIRE incorporates an initial, modified rolling six-dose escalation phase Ib design of up to 36 patients with advanced solid tumours followed by a 20-patient open-label randomised controlled dose expansion phase IIa component as neoadjuvant treatment for UBC. Patients are being recruited from UK secondary care sites. The dose escalation phase will determine a recommended phase II dose (RP2D, primary endpoint) of SGI-110, by subcutaneous injection, on days 1–5 for combination with GC at conventional doses (cisplatin 70 mg/m2, IV infusion, day 8; gemcitabine 1000 mg/m2, IV infusion, days 8 and 15) in every 21-day cycle. In the dose expansion phase, patients will be randomised 1:1 to GC with or without SGI-110 at the proposed RP2D. Secondary endpoints will include toxicity profiles, SGI-110 pharmacokinetics and pharmacodynamic biomarkers, and pathological complete response rates in the dose expansion phase. Analyses will not be powered for formal statistical comparisons and descriptive statistics will be used to describe rates of toxicity, efficacy and translational endpoints by treatment arm.DiscussionSPIRE will provide evidence for whether SGI-110 in combination with GC chemotherapy is safe and biologically effective prior to future phase II/III trials as a neoadjuvant therapy for UBC and potentially in other cancers treated with GC.Trial RegistrationEudraCT Number: 2015–004062-29 (entered Dec 7, 2015)ISRCTN registry number: 16332228 (registered on Feb 3, 2016)

Endostar Combined with Gemcitabine and Cisplatin Chemotherapy for Patients with Metastatic Nasopharyngeal Carcinoma: an Update

OBJECTIVE: A previous phase-2 trial to assess the addition of Endostar to gemcitabine and cisplatin (GC) chemotherapy showed that it improves prognosis in metastatic nasopharyngeal carcinoma (M-NPC) but the study cohort was small. We wished to update that phase-2 trial by enrolling an additional 44 patients and to assess the benefit of Endostar+GC chemotherapy. METHODS: An analysis of 72 M-NPC patients treated between July 2010 and November 2016 was done. The treatment regimen was a combination of gemcitabine (1,000 mg/m2) on days 1 and 8, cisplatin (80 mg/m2) on day 1, and Endostar (15 mg/day) from day 1 to day 14 of a 21-day cycle for ≥2 cycles. The acute toxic effects and therapeutic efficacy were analyzed. RESULTS: The response rate was 77.8%. The median progression-free and overall survivals were 12 and 19.5 months, respectively. A total of 329 cycles of GC and 288 cycles of Endostar were delivered to 72 patients, with the median number of four (range, 2–10) cycles administered per patient. The main grade-3/4 hematologic toxicities were leukopenia (54.1%) and neutropenia (59.8%). The number of non-hematologic adverse events was minimal. The regimen was well-tolerated. CONCLUSIONS: Endostar+GC chemotherapy is an effective, well-tolerated regimen for M-NPC.

MiR34a/GOLPH3 Axis abrogates Urothelial Bladder Cancer Chemoresistance via Reduced Cancer Stemness.

Rationale: Chemoresistance and subsequent recurrence of human urothelial bladder cancer (UBC) is partially driven by a subpopulation of tumor initiating cells, namely cancer stem cells (CSCs). However, the underlying molecular mechanism in chemotherapy-induced CSCs enrichment and following chemoresistance and recurrence remains largely unclear.Methods: Gemcitabine and cisplatin (GC) chemoresistant cell lines (T24 GC 3rd and 5637 GC 3rd cells) and the chemo-sensitive UBC cell lines T24 and 5637 were established in vivo for the investigation of acquired resistance mechanisms. The role of miR34a/GOLPH3 axis in regulating UBC chemoresistance and recurrence was evaluated in cell and animal models. The expression levels of miR34a/GOLPH3 axis and CSCs markers were assayed in specimens of UBC. The association of GOLPH3 with clinicopathologic features and prognosis was analysed.Results: RT-PCR and western blotting confirmed that the expression levels of miR34a were decreased and GOLPH3 were increased in GC chemoresistant UBC cell lines. Downregulation of miR34a resulted in the overexpression of GOLPH3, which is a target gene of miR34a confirmed by luciferase experiment. The ectopic expression of miR34a decreased the stem cell properties of chemoresistant UBC cells and re-sensitized these cells to GC treatment in vitro and in vivo. Moreover, miR34a/GOLPH3 axis has obvious clinical relevance with prognosis and recurrence in human UBC patients with standard GC chemotherapy.Conclusion: Our results suggest that miR34a/GOLPH3 axis exert key role in CSCs involved UBC drug resistance and recurrence and warrant further development as a promising therapeutic approach in treating drug-resistant UBC.

CYLD downregulates Livin and synergistically improves gemcitabine chemosensitivity and decreases migratory/invasive potential in bladder cancer: the effect is autophagy-associated.

Although GC (gemcitabine and cisplatin) chemotherapy remains an effective method for treating bladder cancer (BCa), chemoresistance is a major obstacle in chemotherapy. In this study, we determined whether gemcitabine resistance correlates with migratory/invasive potential in BCa and whether this relationship is regulated by the cylindromatosis (CYLD)-Livin module. First, we independently investigated the correlation of CYLD/Livin and gemcitabine resistance with the potential for tumor migration and invasiveness. Second, we found that co-transfected CYLD and Livin dramatically improved sensitivity to gemcitabine chemotherapy and decreased migration/invasion potential. Next, we determined that CYLD may regulate Livin by the NF-κB-dependent pathway. We also found that CYLD overexpression and Livin knockdown might improve gemcitabine chemosensitivity by decreasing autophagy and increasing apoptosis in BCa cells. Finally, the effects of CYLD-Livin on tumor growth in vivo were evaluated. Our study demonstrates that CYLD-Livin might represent a potential therapeutic for chemoresistant BCa.

Next Generation Sequencing (NGS) to reveal mutations in IDH1 and its effect on patient (pt) outcomes in advanced biliary tract cancer (aBTC) who received gemcitabine and cisplatin (GC).

287 Background: aBTC is uncommon and has a dismal prognosis with limited therapeutic options. First-line therapy for untreated aBTC is GC, with no approved therapies in the refractory setting. To assess for tumor-specific genetic variants that affect outcomes in patients (pts) who received GC in aBTC, we performed NGS in pts treated with who received GC as first-line therapy. Methods: Archival formalin-fixed, paraffin-embedded samples from pts with mBTC from Ohio State University and MD Anderson Cancer Center who received GC in the first-line and underwent NGS as part of routine care. 315 cancer-related genes plus select introns from 28 genes altered in solid tumors were included in the NGS panel. Univariate Cox regression model was used to determine the association between gene mutations with progression free survival (PFS) and (OS). Results: 80 evaluable pts with aBTC treated with first-line GC chemotherapy underwent successful genomic profiling. A total of 414 cancer-specific mutations were identified, where 49 (12%) genes had mutations with &gt; 5% frequency. 17 of the 49 were known mutations. From the comprehensive analysis, somatic mutations in IDH1 (11 of 80 pts; 13%) (HR 0.31; p = 0.035) was associated with improved overall survival (OS) and progression free survival (PFS). Pts wild type for IDH1 had a median OS of 17.7 months and PFS of 4.5 months, while those with an IDH1 mutation had a median OS that was not reached and an improved PFS of 5.7 months. Conclusions: Somatic mutations in IDH1 were associated with improved clinical outcomes in pts with aBTC who received GC as first-line therapy which is consistent with other solid tumor malignancies. IDH1 is a therapeutic target of interest, where future prospective studies will be necessary to validate the predictive utility and its relevance in pt outcomes in aBTC.

Outcomes of palliative weekly low-dose gemcitabine-Cisplatin chemotherapy in anthracycline- and taxane- pretreated metastatic breast cancer patients.

PurposeThe combination of gemcitabine and cisplatin (GP) has been shown to be safe and efficacious for patients with metastatic breast cancer (MBC), pretreated with anthracyclines and taxanes. We assessed the efficacy and safety of weekly low-dose GP in patients with MBC.MethodsWe collected clinicopathological data from MBC patients who had been treated with gemcitabine, 800 mg/m2 plus cisplatin, 30 mg/m2 intravenously, on days 1 and 8 every 3 weeks, between January 2001 and November 2011 in Korea.ResultsThe analysis included 294 patients previously treated anthracycline-xand taxane-based chemotherapies prior to GP (median age, 48 years [range, 28-78 years]; median follow-up duration, 63.9 months). Seventeen patients (5.8%) discontinued GP because of toxicities. The median progression-free survival (PFS) was 3.9 months (95% confidence interval [CI], 3.394.4 months) and the median overall survival (OS) was 27.7 months (95% CI, 17.6-37.8 months) months. Statistically significant factors for PFS were performance status (Eastern Cooperative Oncology Group, ≥2 vs. <2; hazard ratio [HR], 1.37; 95% CI, 1.02-1.85; p=0.037), distant disease-free interval (DDFI; ≤2 years vs. >2 years; HR, 1.66; 95% CI, 1.28-1.95, p<0.001), time interval from the diagnosis of metastasis to GP therapy (≤1 year vs. >1 year; HR, 1.48; 95% CI, 1.13-1.95, p<0.001), and presence of brain metastasis (HR, 1.47; 95% CI, 1.03-2.10; p=0.031). Similarly, DDFI (≤2 years vs. >2 years; HR, 2.07; 95% CI, 1.36-3.14; p<0.001) and the presence of brain metastasis (HR, 2.14; 95% CI, 1.27-3.61; p=0.004) were important factors for OS after GP treatment.ConclusionWeekly low-dose GP chemotherapy appears safe and effective for heavily pretreated MBC patients.

Pathologic response rates between gemcitabine-cisplatin (GC) and methotrexate, vinblastine, doxorubicin hydrochloride, and cisplatin (MVAC) neoadjuvant chemotherapy in muscle-invasive urothelial cell carcinoma of the bladder.

267 Background: Neoadjuvant chemotherapy for muscle invasive urothelial carcinoma (UC) of the bladder is associated with higher rates of pathologic complete response (CR) and improved disease-specific survival compared to those treated with radical cystectomy (RC) alone. Two standard regimens used are (1) gemcitabine and cisplatin (GC); and (2) methotrexate, vinblastine, adriamycin, and cisplatin (MVAC), with debate on whether there is a difference in clinical efficacy. In this analysis, we compare the pathologic outcomes at cystectomy between neoadjuvant GC and MVAC treatment. Methods: Data was retrospectively collected on patients with T2-T4 UC of the bladder who underwent RC between Sept 2003 and December 2011 at the University of Washington. Clinical and pathologic factors were recorded along with neoadjuvant chemotherapy and comorbidities. Pathologic outcomes included those with CR (pT0) and near CR (nCR = pT0/Ta/Tis). Odds ratio (OR) for CR and nCR were calculated using multivariate logistic regression adjusting for demographic (age, gender, race), medical (creatinine, diabetes mellitus, cardiac disease) and clinical factors (clinical T stage, prior BCG therapy, complete tumor debulking prior to chemotherapy). Results: A total of 78 patients received GC or MVAC neoadjuvant chemotherapy followed by RC, including 46 who received GC and 32 who received MVAC. There was no difference in gender, renal function, cardiac disease or clinical stage between the two groups. Patients over 70 years of age primarily received GC (17/18). CR was achieved in 30% and 25% (p = 0.15) of GC and MVAC patients, respectively (multivariate OR 0.42, 95% CI 0.11-1.63). nCR was more common in those receiving GC (50% vs. 38%, p = 0.04) although non-significant in the multivariate model (OR 0.30, 95% CI 0.07-1.16). Conclusions: We observed similar pathologic response rates for GC and MVAC neoadjuvant chemotherapy in this cohort of bladder cancer patients. These observations support the use of GC as an alternative regimen in the neoadjuvant setting.

Pathologic Response Rates of Gemcitabine/Cisplatin versus Methotrexate/Vinblastine/Adriamycin/Cisplatin Neoadjuvant Chemotherapy for Muscle Invasive Urothelial Bladder Cancer

Objectives. To compare pathologic outcomes after treatment with gemcitabine and cisplatin (GC) versus methotrexate, vinblastine, adriamycin, and cisplatin (MVAC) in the neoadjuvant setting. Methods. Data was retrospectively collected on 178 patients with T2-T4 bladder cancer who underwent radical cystectomy between 2003 and 2011. Outcomes of interest included those with complete response (pT0) and any response (≤pT1). Odds ratios were calculated using multivariate logistic regression. Results. Compared to those who did not receive neoadjuvant chemotherapy, there were more patients with complete response (28% versus 9%, OR 3.11 (95% CI: 1.45–6.64), P = 0.03) and any response (52% versus 25%, OR 3.23 (95% CI: 1.21–8.64), P = 0.01). Seventy-two patients received GC (n = 41) or MVAC (n = 31). CR was achieved in 29% and 22% of GC and MVAC patients, respectively (multivariate OR 0.39, 95% CI 0.10–1.58). Any response (≤pT1) was achieved in 56% of GC and 45% of MVAC patients (multivariate OR 0.45, 95% CI 0.12–1.71). Conclusions. We observed similar pathologic response rates for GC and MVAC neoadjuvant chemotherapy in this cohort of patients with muscle invasive urothelial cancer (MIBC). Our findings support the use of GC as an alternative regimen in the neoadjuvant setting.