Meta-analysis of gemcitabine in brief versus prolonged low-dose infusion for advanced non-small cell lung cancer

Zhao, Dehua; Mingming, Chu; Wang, Jisheng

doi:10.1371/journal.pone.0193814

Cited by 5 publications

(4 citation statements)

References 21 publications

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“…Multiple small underpowered studies prior to ours have tried to address this question and a recent meta analysis of these studies suggested that low dose gemcitabine with prolonged infusion leads to a similar 1 year OS and has a lower rate of leukopenia and thrombocytopenia [12], [13], [14], [20], [21], [22], [23]. However, the authors had cautioned that the evidence was of low quality and a high quality large trial was required to answer this question and to test the validity of their results.…”

Section: Discussionmentioning

confidence: 98%

Phase III Non-inferiority Study Evaluating Efficacy and Safety of Low Dose Gemcitabine Compared to Standard Dose Gemcitabine With Platinum in Advanced Squamous Lung Cancer

et al. 2019

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Background Prolonged infusion of low dose gemcitabine (PLDG) in combination with platinum has shown promising activity in terms of improved response rate and progression free survival (PFS); especially in squamous non-small cell lung cancer (NSCLC). Hence, we conducted a phase 3 randomized non-inferiority study with the primary objective of comparing the overall survival (OS) between PLDG and standard dose of gemcitabine with platinum. Methodology Adult subjects (age ≥ 18 years), with stages IIIB–IV, NSCLC (squamous) and ECOG performance status of ≤ 2 were randomized 1:1 into either carboplatin with standard dose gemcitabine (1000 mg/m 2 intravenous over 30 min, days 1 and 8) (STD-G arm) or carboplatin along with low dose gemcitabine (250 mg/m 2 intravenous over 6 h, days 1 and 8) (LOW-G arm) for a maximum of 6 cycles. Tumor response was assessed by RECIST criteria version 1.1 every 2 cycles till 6th cycle and thereafter at 2 monthly intervals till progression. The primary endpoint was overall survival. 308 patients were randomized, 155 in STD-G arm and 153 in LOW-G arm, respectively. Results The median overall survival in STD-G arm was 6.8 months (95%CI 5.3–8.5) versus 8.4 months (95%CI 7–10.3) in the LOW-G arm (HR-0.890 (90%CI 0.725–1.092). The results with per protocol analysis were in line with these results. There was no statistical difference in progression free survival (HR-0.949; 90%CI 0.867–1.280) and adverse event rate between the 2 arms. Conclusion This study suggests that PLDG is an alternative to the standard gemcitabine schedule in squamous NSCLC, and either of these can be selected subject to patient convenience.

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Section: Discussionmentioning

confidence: 98%

Phase III Non-inferiority Study Evaluating Efficacy and Safety of Low Dose Gemcitabine Compared to Standard Dose Gemcitabine With Platinum in Advanced Squamous Lung Cancer

et al. 2019

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“…Furthermore, oral gemcitabine administration would allow for greater flexibility in designing dosing schedules, enabling both metronomic gemcitabine dosing (i.e., frequent low dose administration) and dosing which replicates gemcitabine pharmacokinetics following a prolonged intravenous infusion. There is evidence that such dosing schedules may lead to improvements in efficacy and/or reductions in toxicity [14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of gemcitabine and its amino acid ester prodrug following intravenous and oral administrations in mice

Thompson

Shi

Zhu

et al. 2020

Biochemical Pharmacology

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Gemcitabine is an intravenously administered anti-cancer nucleoside analogue. Systemic exposure following oral administration of gemcitabine is limited by extensive first-pass metabolism via cytidine deaminase (CDA) and potentially by saturation of nucleoside transporter-mediated intestinal uptake. An amino acid ester prodrug of gemcitabine, 5'-l-valylgemcitabine (V-Gem), was previously shown to be a substrate of the intestinally expressed peptide transporter 1 (PEPT1) and stable against CDA-mediated metabolism. However, preliminary studies did not evaluate the in vivo oral performance of V-Gem as compared to parent drug. In the present study, we evaluated the pharmacokinetics and in vivo oral absorption of gemcitabine and V-Gem following intravenous and oral administrations in mice. These studies revealed that V-Gem undergoes rapid systemic elimination (half-life < 1 min) and has a low oral bioavailability (< 1%). Most importantly, the systemic exposure of gemcitabine was not different following oral administration of equimolar doses of gemcitabine (gemcitabine bioavailability of 18.3%) and V-Gem (gemcitabine bioavailability of 16.7%). Single-pass intestinal perfusions with portal blood sampling in mice revealed that V-Gem undergoes extensive activation in intestinal epithelial cells and that gemcitabine undergoes first-pass metabolism in intestinal epithelial cells. Thus, formulation of gemcitabine as the prodrug V-Gem does not increase systemic gemcitabine exposure following oral dosing, due, in part, to the instability of V-Gem in intestinal epithelial cells.

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“…In clinical practice, Gem administered as a 30-min infusion of 1,000–1,250 mg/m 2 is the standard regimen. However, several trials 9 – 12 have demonstrated that another type of administration [prolonged low-dose infusion (P-LDI)] exhibits a comparable activity and toxicity compared with a 30-min infusion of the standard dose (30-min SDI). Previously, we suggested that P-LDI was superior in terms of the overall response rate, experienced less grade 3/4 thrombocytopenia and leukopenia compared with 30-min SDI, and could be a viable treatment option for advanced NSCLC.…”

Section: Introductionmentioning

confidence: 99%

“…Previously, we suggested that P-LDI was superior in terms of the overall response rate, experienced less grade 3/4 thrombocytopenia and leukopenia compared with 30-min SDI, and could be a viable treatment option for advanced NSCLC. 9 However, whether the same is also applicable to other cancer types remains unclear. Hence, this systematic review of the current literature aims to provide some references for Gem administered as a prolonged infusion and supports the need for further investigation regarding both clinical efficiency and safety.…”

Section: Introductionmentioning

confidence: 99%

<p>Prolonged low-dose infusion for gemcitabine: a systematic review</p>

Zhao

Chen

Mingming

et al. 2019

OTT

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Background The present standard dose of gemcitabine (Gem), a pyrimidine antimetabolite, is 1,000–1,250 mg/m 2 , and the infusion time is 30 min. However, pharmacological studies have demonstrated that Gem with prolonged infusion could attain a better accumulation rate of Gem triphosphate (active metabolites of Gem), indicating that Gem with prolonged infusion is superior to 30-min infusion. Thus, this systematic review aims to provide some references for Gem administered as a prolonged infusion. Methods We searched electronic databases, including PubMed, EMBASE, Cochrane Library, and CNKI, for trials. Keywords were “Gem,” “prolonged infusion,” and “low-dose.” In addition, we used the Cochrane Handbook V5.1.0 and methodological index for non-randomized studies to evaluate the quality of randomized controlled trials (RCTs) and non-RCTs, respectively. Furthermore, Cochrane Collaboration guidelines and the PRISMA statement were adopted. Results We systematically reviewed 19 studies (5 RCTs and 14 non-RCTs). All studies assessed the efficacy and safety of Gem administered as a prolonged low-dose infusion (P-LDI) and reported that Gem administered as P-LDI was effective and well tolerated. Conclusion Gem administered as P-LDI is effective, safe, and economical, especially suited for patients with poor performance status or without good economic condition.

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Meta-analysis of gemcitabine in brief versus prolonged low-dose infusion for advanced non-small cell lung cancer

Cited by 5 publications

References 21 publications

Phase III Non-inferiority Study Evaluating Efficacy and Safety of Low Dose Gemcitabine Compared to Standard Dose Gemcitabine With Platinum in Advanced Squamous Lung Cancer

Phase III Non-inferiority Study Evaluating Efficacy and Safety of Low Dose Gemcitabine Compared to Standard Dose Gemcitabine With Platinum in Advanced Squamous Lung Cancer

Pharmacokinetics of gemcitabine and its amino acid ester prodrug following intravenous and oral administrations in mice

<p>Prolonged low-dose infusion for gemcitabine: a systematic review</p>

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