Gemcitabine

Background: Gemcitabine/nab-paclitaxel (GN) and FOLFIRINOX (FFX) are two standard first-line therapies for metastatic pancreatic cancer (PC) but have rarely been compared, especially in patients with locally advanced PC (LAPC). Methods: This is a retrospective European multicenter study including patients with LAPC treated with either GN or FFX as the first-line therapy between 2010 and 2019. Coprimary objectives were progression-free survival (PFS) and overall survival (OS), both estimated using the Kaplan–Meier method. Results: A total of 147 patients (GN: n = 60; FFX: n = 87) were included. Tumor resection rates were similar between the two groups (16.7% vs. 16.1%; p = 1), with similar R0 resection rates (88.9%). Median PFS rates were not statistically different: 9 months (95% CI: 8–13.5) vs. 12.1 months (95% CI: 10.1–14.6; p = 0.8), respectively. Median OS rates were 15.7 months (95% CI: 12.6–20.2) and 16.7 months (95% CI: 14.8–20.4; p = 0.7), respectively. Abdominal pain at the...

The non-nucleoside analog gemcitabine has been the standard of care for treating pancreatic cancer. The drug shows good potency in pancreatic cancer cells in vitro but, due to poor bioavailability, requires administration in large doses by infusion and this systemic exposure results in significant toxicity for the patient. Genes have been identified that, when silenced by siRNA, synergize with gemcitabine treatment and offer a means of reducing the gemcitabine dosage required for efficacy. However, benefiting from the synergism between the two agents requires that the gemcitabine and siRNA penetrate the same cells. To ensure co-delivery, we incorporated gemcitabine covalently within siRNAs against targets synergistic with gemcitabine (CHK1 or RAD17). We demonstrated that specific bases within an siRNA can be replaced with gemcitabine to increase efficacy. The result is a single drug molecule that simultaneously co-delivers gemcitabine and a synergistic siRNA. The siRNA–gemcitabine constructs demonstrate a 5–30-fold improvement in potency compared with gemcitabine alone. Co-delivering a CHK1 siRNA–gemcitabine construct together with a WEE1 siRNA resulted in a 10-fold improvement in IC50 compared with gemcitabine alone. These constructs demonstrate efficacy across a wide array of pancreatic tumor cells and may represent a novel therapeutic approach for treating pancreatic cancer.

Pancreatic cancer is one of the most lethal cancer. Developing early screening tools can help in diagnosing pancreatic cancer at earlier stages when surgical resection is still a possibility leading to more years of survival and a potential cure. Here a review is presented about CA 19-9 and some other pancreatic adenocarcinoma serum tumor markers including THBS2, MIC-1, sTRA, CEACAM1, CA 494, Span-1, and PAM4 that show some improvement over CA19-9. A combination of these serum markers in screening tests may yield more sensitive and specific results that can be used for screening high risk as well as the general population. The effectiveness of chemotherapeutic drugs is limited in pancreatic cancer. There is a likelihood that the combination of standard chemotherapy with natural compounds having anti-cancer potential like curcumin will increase the effectiveness of treatment as well as reduce the toxic side effects of standard chemotherapeutic agents. Another review is presented about the potential use of curcumin with standard chemotherapy in pancreatic cancer to increase median survival in pancreatic cancer in comparatively less toxic, novel ways.

Pancreatic cancer is one of the most lethal cancer and there is innate resistance to standard chemotherapy regimens in pancreatic cancer. Gemcitabine was approved in 1996 for the chemotherapeutic treatment of metastatic pancreatic cancer. FOLFIRINOX (fluorouracil, leucovorin, irinotecan, oxaliplatin) and gemcitabine plus nab-paclitaxel combination therapies have shown superiority to gemcitabine monotherapy but are more toxic than gemcitabine monotherapy. Therefore, gemcitabine monotherapy is still one of the standard treatments for pancreatic cancer for patients who can't tolerate the toxicity of other chemotherapeutic regimens. The effectiveness of standard chemotherapeutic drugs is limited in pancreatic cancer due to drug resistance, and undesirable side effects. There is a likelihood that the combination of standard chemotherapy with natural compounds having anti-cancer potential like curcumin will increase the effectiveness of treatment as well as reduce the toxic side effects of standard chemotherapeutic agents. Curcumin is a polyphenolic compound isolated from the rhizome of Curcuma longa (turmeric) and is considered a promising anticancer agent. Here, a review is presented about the potential use of curcumin with standard chemotherapy in pancreatic cancer as there is a potential in different combination regimens of curcumin in pancreatic cancer to increase median survival in pancreatic cancer in comparatively less toxic, novel ways. Also, curcumin combination chemotherapy may lead to the improvement of cancer and chemotherapy-related symptoms. The poor bioavailability of curcumin has been the major obstacle for its clinical application. To overcome this problem, several curcumin preparations have been developed including cost-effective preparation methods to increase the bioavailability of curcumin. Different studies have shown that gemcitabine curcumin combination regimen can effectively increase survival with less toxicity in patients who are resistant to gemcitabine and can't even tolerate the toxicity of other chemotherapeutic combination regimens. Although clinical trials are needed, Paclitaxel and curcumin cobound albumin nanoparticles also have the potential to become another alternative chemotherapeutic regimen for pancreatic cancer. For those patients who can tolerate gemcitabine paclitaxel regimen toxicity, there can also be a future possibility of using paclitaxel and curcumin cobound albumin nanoparticles with gemcitabine and this triple therapy may have enhanced therapeutic effects with comparatively less toxic effects. Curcumin has shown its effectiveness with the constituents of FOLFIRINOX in other types of cancers, therefore there is a need for curcumin FOLFIRINOX combined clinical trials in pancreatic cancer as curcumin has the potential to increase the effectiveness of FOLFIRINOX as well as reduce its toxic side effects.

OBJECTIVE To Jnvest~gate the relationship between body mass ~ndex (BMI) and tung cancer risk among men in urban Shanghai, China. METHODS Between January 1,1986 and September 30,1989, a total of 18,244 male readents of urban Shanghai were recruited in the prospective cohort study. The eligible study subjects were those aged 45 to 64 years and w~thout history of cancer. Through July 10 ''~, 2003 (17 years follow-up), 467 new cases of lung cancer were identified in the cohort. Cox regression models were used to estimate the adjusted relative risks (RRs) and 95% confidence intervals (CIs). RESULTS The risk of lung cancer decreased with increasing in BMI. After adjustment for some potential confounding factors, a relative risk of 0.6 (highest versus lowest quintile of BMI) was observed (P-trend =0.01). Stratified by smoking status, an inverse association of body mass index with lung cancer risk still existed among current smokers. There were too few cases of tung cancer to draw...

Pancreatic cancer is one of the most lethal cancer and there is innate resistance to standard chemotherapy regimens in pancreatic cancer. Gemcitabine was approved in 1996 for the chemotherapeutic treatment of metastatic pancreatic cancer. FOLFIRINOX (fluorouracil, leucovorin, irinotecan, oxaliplatin) and gemcitabine plus nab-paclitaxel combination therapies have shown superiority to gemcitabine monotherapy but are more toxic than gemcitabine monotherapy. Therefore, gemcitabine monotherapy is still one of the standard treatments for pancreatic cancer for patients who can’t tolerate the toxicity of other chemotherapeutic regimens. The effectiveness of standard chemotherapeutic drugs is limited in pancreatic cancer due to drug resistance, and undesirable side effects. There is a likelihood that the combination of standard chemotherapy with natural compounds having anti-cancer potential like curcumin will increase the effectiveness of treatment as well as reduce the toxic side effects o...

Pancreatic cancer has a poor prognosis, mainly due to lack of effective therapies. This study demonstrated the ability of dietary agent, indole-3-carbinol (I3C), to lower the LD(50) of gemcitabine (Gemzar) in decreasing growth of both male (MiaPaca2) and female (SU86.86) pancreatic cancer cells. Female pancreatic cancer cells were more resistant to gemcitabine alone. Additionally, RT-PCR analysis of MiaPaca2 cells treated with 1, 10 or 100 μM of I3C showed that I3C reactivated the tumor suppressor gene p16INK4a in pancreatic cancer cells. Methylated-specific PCR analysis indicated that I3C demethylated the promoter region of p16 INK4a, which was methylated in the untreated cancer cells. p16INK4a inactivation through promoter hypermethylation is considered an early event in pancreatic carcinogenesis. A positive control using 5-azacytidine also reactivated p16INK4a. This study demonstrated the potential of I3C, a possible non-toxic hypomethylating agent, combined with the anticancer a...

Sonic hedgehog (SHH), an activating ligand of smoothened (SMO), is overexpressed in > 70% of pancreatic cancers (PCs). We investigated the impact of vismodegib, an SHH antagonist, plus gemcitabine (GV) or gemcitabine plus placebo (GP) in a multicenter phase Ib/randomized phase II trial and preclinical PC models. Patients with PC not amenable to curative therapy who had received no prior therapy for metastatic disease and had Karnofsky performance score ≥ 80 were enrolled. Patients were randomly assigned in a one-to-one ratio to GV or GP. The primary end point was progression-free-survival (PFS). Exploratory correlative studies included serial SHH serum levels and contrast perfusion computed tomography imaging. To further investigate putative biologic mechanisms of SMO inhibition, two autochthonous pancreatic cancer models (Kras(G12D); p16/p19(fl/fl); Pdx1-Cre and Kras(G12D); p53(R270H/wt); Pdx1-Cre) were studied. No safety issues were identified in the phase Ib portion (n = 7), a...

Context Gemcitabine is the backbone of systemic treatment of locally advanced and metastatic intrahepatic cholangiocarcinoma. In recent literature, gemcitabine has been linked to various pulmonary side effects.
Case Report We report a case of an 82-year-old male who developed acute pulmonary hypertension after receiving one cycle of gemcitabine for metastatic cholangiocarcinoma. His symptoms began with fatigue associated with shortness of breath and cough that worsened despite dose reduction. He developed new onset bilateral pulmonary effusions and an echocardiogram revealed findings consistent with pulmonary hypertension. A computed tomography (CT) angiogram was negative for pulmonary thromboembolism. Although he was promptly treated with diuretics and steroids, the patient could not tolerate any further therapy.
Conclusion Gemcitabine-induced pulmonary hypertension is rare and can be challenging to diagnose, as it remains a diagnosis of exclusion. However, physicians should be vigilant of new pulmonary symptoms, as delayed treatment can cause significant patient morbidity and mortality.

Gemcitabine (Gem) is the standard of treatment for metastatic pancreatic ductal adenocarcinoma (PDAC) and an effective anticancer drug for various solid tumors. However, clinical application of Gem chemotherapy is hampered by suboptimal delivery of the drug, mainly due to short circulation time and poor penetration of drug into the hypo-vascularized and dense fibrous stroma of PDAC. Here, we present a novel method to improve both loading and stability of Gem in temperature-sensitive liposomes (TSL). TSL have the potential to be locally activated by exposing tumor to ultrasound-mediated hyperthermia (USH) triggering release of large amounts of free drug in the tumor vasculature, which can then rapidly penetrate into the heated tumor. Gem was passively loaded into TSL composed of DPPC:DSPC:DSPE-PEG2k (80:15:5) in the presence of copper(II) gluconate and triethanolamine at final 0.12 mg-drug/mg-lipid. Formation of a CuGem complex improved drug loading and stability and reduced systemic toxicity. Mice with bilateral invasive neu deletion (NDL) tumors (4-5 mm) were treated with an i.v. administration of CuGem-TSL at 10 mg Gem/kg body weight. USH was employed to trigger the release of drug; one tumor in the bilateral tumor model was insonified with a peak ultrasound pressure of 1.1 MPa at a frequency of 1.5 MHz at 43°C for 5 min prior to and 30 min post drug injection with a variable duty cycle. We found that copper(II) gluconate possesses superior potential to solubilize Gem up to 150 mg/mL and augments passive drug loading. Upon loading Gem, formation of a complex with copper further improved drug loading and stability within TSL. By optimizing the lipid composition of the liposomal shell, we achieved high loading content of Gem at up to 12% by weight in TSL (CuGem-TSL), 4-fold greater than previously reported. Cryo electron microscopy confirmed the presence of liquid crystalline structures within CuGem-TSL, which was not observed in the absence of copper (Gem-TSL). The resulting high-content CuGem-TSL displayed a rapid release of Gem (80%) within 5 min at 42°C with only 25% release over 30 min at 37°C in the presence of serum. In vitro CuGem-TSL demonstrated equivalent toxicity to free Gem against both murine breast cancer and pancreatic cancer. One hour following intravenous administration, 75% of Gem was effectively retained in circulating TSL, whereas no drug was detected in mouse plasma with free drug administration. Three repeated administrations of CuGem-TSL combined with USH over a two-week treatment course suppressed tumor growth in NDL, model of murine breast cancer, with limited toxicity, enhancing survival when compared to treatment with free Gem alone. Additionally, in a more aggressive tumor model of murine pancreatic cancer (KrasLSL-G12D/+; Trp53LSL-R172H/+; Pdx-Cre, mT4 tumor source), CuGem-TSL with USH induced cell death and regions of apoptosis and necrosis. Citation Format: Samantha T. Tucci, Azadeh Kheirolomoom, Elizabeth S. Ingham, Lisa M. Mahakian, Sarah M. Tam, Josquin Foiret, Neil E. Hubbard, Alexander D. Borowsky, Mo Baikoghli, R. Holland Cheng, Katherine W. Ferrara. Activatable nanodelivery of high payload gemcitabine augments therapeutic efficacy in murine breast and pancreatic cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2171.

We investigated the safety, efficacy and pharmacokinetics of the intravesical administration of 2000 mg gemcitabine once a week in the four weeks before transurethral resection of superficial bladder cancer (TUR), and in the four successive weeks. Nine patients with superficial transitional cell bladder carcinoma were studied. Two thousand mg of gemcitabine dissolved in 50 ml of distilled water were administered intravesically. The dwell time was 60 min. The pharmacokinetics of gemcitabine and its metabolite, 2',2'-difluorodeoxyuridine (dFdU), were studied in plasma and urine before and after TUR. Cystoscopy was repeated 30 days after completion of the TUR treatment and subsequently at time intervals of one or two months. No systemic toxicity was noted, and only three patients displayed modest signs of local toxicity. One patient had recurrence 1 month after TUR, three between 3 and 6 months, and another three after 8, 11 and 18 months, respectively; two were recurrence-free...

BACKGROUND The 2020 National Comprehensive Cancer Network guidelines recommend neoadjuvant FOLFIRINOX or neoadjuvant gemcitabine plus nab-paclitaxel (G-nP) for borderline resectable/locally advanced pancreatic ductal adenocarcinoma (BR/LA PDAC). AIM The purpose of our study was to compare treatment outcomes, toxicity profiles, costs, and quality-of-life measures between these two treatments to further inform clinical decision-making. METHODS AND RESULTS We developed a decision-analytic mathematical model to compare the total cost and health outcomes of neoadjuvant FOLFIRINOX against G-nP over 12 years. The model inputs were estimated using clinical trial data and published literature. The primary endpoint was incremental cost-effectiveness ratios (ICERs) with a willingness-to-pay threshold of $100 000 per quality-adjusted-life-year (QALY). Secondary endpoints included overall (OS) and progression-free survival (PFS), total cost of care, QALYs, PDAC resection rate, and monthly treatment-related adverse events (TRAE) costs (USD). FOLFIRINOX was the cost-effective strategy, with an ICER of $60856.47 per QALY when compared to G-nP. G-nP had an ICER of $44639.71 per QALY when compared to natural history. For clinical outcomes, more patients underwent an "R0" resection with FOLFIRINOX compared to G-nP (84.9 vs. 81.0%), but FOLFIRINOX had higher TRAE costs than G-nP ($10905.19 vs. $4894.11). A one-way sensitivity analysis found that the ICER of FOLFIRINOX exceeded the threshold when TRAE costs were higher or PDAC recurrence rates were lower. CONCLUSION Our modeling analysis suggests that FOLFIRNOX is the cost-effective treatment compared to G-nP for BR/LA PDAC despite having a higher cost of total care due to TRAE costs. Trial data with sufficient follow-up are needed to confirm our findings.