Liposomal irinotecan in gemcitabine-refractory metastatic pancreatic cancer: efficacy, safety and place in therapy
28
Citation
54
Reference
10
Related Paper
Citation Trend
Abstract:
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease. The majority of patients are diagnosed with locally advanced or metastatic disease with a prognosis of short months. Therapeutic options are limited and until recently, there was no standard second-line chemotherapy option. Liposomal constructs have been engineered to encapsulate chemotherapy thereby preventing premature metabolism, improving distribution and minimizing toxicity. Favourable preclinical data on liposomal irinotecan and early phase trials, led to a recently published phase III trial of liposomal irinotecan in combination with fluorouracil and folinic acid in patients with metastatic PDAC, who progressed after gemcitabine-based chemotherapy. As a direct result, the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) have approved the use of liposomal irinotecan in this setting. However, first-line treatment options for this disease now include the combination regimen, FOLFIRINOX, in patients with good performance status, and the role of second-line combination treatment with liposomal irinotecan in this setting is unclear. Recent advances have changed the therapeutic landscape, as clinicians are now able to choose a sequential approach to treatment tailored to the individual patient characteristics. This article reviews current treatment options for metastatic PDAC and focuses on the efficacy, safety and place in therapy of liposomal irinotecan.Keywords:
FOLFIRINOX
Regimen
There are no randomized data to guide treatment decisions for patients with advanced pancreatic adenocarcinoma following first-line FOLFIRINOX. We performed a systematic review and meta-analysis of studies using gemcitabine-based chemotherapy after FOLFIRINOX to assess treatment efficacy and toxicity.We included studies published between 2011 and 2018 that evaluated the efficacy and toxicity of gemcitabine-based chemotherapy after FOLFIRINOX in patients with advanced pancreatic adenocarcinoma. We searched PubMed, Embase, Scopus, and Web of Science. Primary outcomes were objective response rate (ORR), disease control rate (DCR), any grade 3/4 toxicity rate, and progression-free survival (PFS). We used the random-effects model to generate pooled estimates for proportions.Sixteen studies met the eligibility criteria. Overall, ORR was 10.8%, DCR was 41.1%, and any grade 3/4 toxicity rate was 28.6%. In subgroup analyses, gemcitabine plus nab-paclitaxel was associated with superior ORR (14.4 versus 8.4%; p = 0.038) and DCR (53.5 versus 30.5%; p < 0.001) compared with single-agent gemcitabine. Median PFS ranged from 1.9 to 6.4 months and numerically favored gemcitabine plus nab-paclitaxel.Our study suggests gemcitabine-based chemotherapy likely outperforms best supportive care after FOLFIRINOX in advanced pancreatic cancer. Also, gemcitabine plus nab-paclitaxel seems to be more active than single-agent gemcitabine (CRD42018100421).
FOLFIRINOX
Cite
Citations (29)
Standard treatment for advanced pancreatic cancer has had minimal impact on natural course of the disease. Current standard chemotherapy for healthy, robust patients remains FOLFIRINOX (5fluorouracil, leucovorin, oxaliplatin, and irinotecan) chemotherapy which showed 4-month overall survival benefit compared to gemcitabine alone [2]. Recently MPACT study showed that adding nabpaclitaxel to gemcitabine significantly improved overall survival compared to gemcitabine (8.5 months vs. 6.7 months P=0.000015). However, the combination remains more toxic compared to gemcitabine [3].
FOLFIRINOX
Cite
Citations (2)
Pancreatic cancer is one of the highly aggressive malignant diseases worldwide. To achieve better treatment outcome of pancreatic cancer, in the current study we explore the underlying molecular mechanism of drug resistance in pancreatic cancer cells. We found that resistance to gemcitabine is associated with epithelial-mesenchymal transition (EMT) phenotype in a panel of pancreatic cancer cell lines. Notably, gemcitabine-resistant pancreatic cancer cells acquire EMT phenotype. Moreover, gemcitabine-resistant cells have increased migration and invasion activities. Furthermore, we observed the high expression of HIF-1α in gemcitabine-resistant cells. More importantly, inhibition of HIF-1α in gemcitabine-resistant cells caused partial reversal of EMT phenotype, suggesting that HIF-1α was critically involved in gemcitabine-resistant-mediated EMT. Therefore, targeting HIF-1α could be an effective strategy for the treatment of pancreatic cancer.
Cite
Citations (48)
FOLFIRINOX (oxaliplatin, irinotecan, 5-fluorouracil, and leucovorin) combination chemotherapy is the gold-standard therapy for advanced pancreatic cancer. In this study, FOLFIRINOX dosages for Japanese patients were established enabling FOLFIRINOX therapy optimization for efficient use.Patients with advanced pancreatic cancer were treated with varying doses of FOLFIRINOX to determine the optimum dosage for highest remission outcomes with the least post-chemotherapy toxicities.Patients given 180 mg of irinotecan and a 400 mg bolus of 5-fluorouracil (5-FU) showed a marked difference in outcome when compared to irinotecan 180 mg given without the 5-FU bolus, with the overall response rate being 28%, a survival time of 6.4 months and progression-free survival time of 4.5 months.The optimum dose of FOLFIRINOX was a dosage combination of oxaliplatin 85 mg/m 2 , irinotecan 180 mg/m 2 , l-leucovorin 400 mg/m 2 and 5-FU 2,400 mg/m 2 , administered as a continuous 46-h infusion.
FOLFIRINOX
Bolus (digestion)
Cite
Citations (2)
Survival rate for pancreatic cancer remains poor and newer treatments are urgently required. Selenium, an essential trace element, offers protection against several cancer types and has not been explored much against pancreatic cancer specifically in combination with known chemotherapeutic agents. The present study was designed to investigate selenium and Gemcitabine at varying doses alone and in combination in established pancreatic cancer cell lines growing in 2D as well as 3D platforms. Comparison of multi-dimensional synergy of combinations' (MuSyc) model and highest single agent (HSA) model provided quantitative insights into how much better the combination performed than either compound tested alone in a 2D versus 3D growth of pancreatic cancer cell lines. The outcomes of the study further showed promise in combining selenium and Gemcitabine when evaluated for apoptosis, proliferation, and ENT1 protein expression, specifically in BxPC-3 pancreatic cancer cells in vitro.
Cite
Citations (8)
Abstract Background UGT1A1 *28 and *6 polymorphism is associated with reduced enzyme activity and severe toxicities of irinotecan, especially in patients with homozygous or heterozygous for UGT1A1*28 or *6 polymorphism for both UGT1A1*28 and *6 (double-variant-type of UGT1A1 polymorphism, UGT1A1-DV). FOLFIRINOX is one of the standard treatments for metastatic pancreatic cancer (PC). The optimal dose of irinotecan as a component of the FOLFIRINOX has not been established yet for patients with UGT1A1-DV. Patients and methods Advanced PC patients with UGT1A1-DV who had received at least one cycle of FOLFIRINOX from December 2013 to March 2016 were collected retrospectively conducted at multicenter in Japan. We evaluated the patient characteristics, efficacy and safety of FOLFIRINOX and investigate the optimal initial dose of irinotecan in Japanese advanced PC patients with UGT1A1-DV. Results A total of 31 patients were enrolled. Grade 4 neutropenia was seen more frequently (67%; 4/6) in patients who had received irinotecan at an initial dose of ≥ 150 mg/m 2 than in those who had received the drug at an initial dose of ≤ 120 mg/m 2 (20%; 5/24). The response rate (RR) and progression-free survival (PFS) in patients given irinotecan of ≤ 120 mg/m 2 were 21.4% and 8.1 months, respectively, which were consistent with previous report for patients without UGT1A1-DV. Conclusion Based on our findings, we recommend that in Japanese advanced PC patients with UGT1A1- DV treated with FOLFIRINOX, irinotecan be administered at an initial dose of ≤ 120 mg/m 2 .
FOLFIRINOX
Camptothecin
Cite
Citations (7)
Introduction: Despite a clinically relevant, statistically significant survival benefit with nab -paclitaxel plus gemcitabine and FOLFIRINOX vs single-agent gemcitabine for metastatic pancreatic cancer (mPC), little is known regarding their real-world effectiveness. We analyzed patients with mPC using a nationally representative electronic medical records database to address this unmet need. Methods: This retrospective analysis of the Navigating Cancer database compared outcomes among patients who received first-line nab -paclitaxel plus gemcitabine, FOLFIRINOX, or gemcitabine for mPC. Effectiveness, safety, and supportive care use were examined. nab -Paclitaxel plus gemcitabine was the reference for statistical comparisons. Results: Baseline characteristics were similar except age (oldest patients were in the gemcitabine cohort followed by nab -paclitaxel plus gemcitabine, then FOLFIRINOX). Patients receiving nab -paclitaxel plus gemcitabine (n=122) demonstrated similar time to treatment discontinuation (TTD; median, 3.4 vs 3.8 months; P =0.947) and database persistence (DP; median, 8.6 vs 8.6 months; P =0.534) vs FOLFIRINOX (n=80); however, TTD (median, 3.4 vs 2.2 months; P <0.001) and DP (median, 8.6 vs 5.3 months; P =0.030) were significantly longer with nab -paclitaxel plus gemcitabine vs gemcitabine (n=46). There were more any-grade adverse events with FOLFIRINOX or gemcitabine vs nab -paclitaxel plus gemcitabine (95% or 89% vs 84%, respectively). Conclusion: This real-world analysis confirms the phase III MPACT trial findings and demonstrates that nab -paclitaxel plus gemcitabine has effectiveness similar to that of FOLFIRINOX but greater tolerability for treating mPC despite younger patients being in the FOLFIRINOX cohort. These findings support nab -paclitaxel plus gemcitabine as an appropriate first-line treatment option for patients with mPC. Keywords: metastatic pancreatic cancer, nab -paclitaxel, gemcitabine, FOLFIRINOX, comparative effectiveness
FOLFIRINOX
Tolerability
Cite
Citations (33)
Objective To investigate the differentially expressed circulating microRNAs of pancreatic cancer,and of the pancreatic cancer with gemcitabine resistance,to find potential biomarkers for noninvasive diagnosis of pancreatic cancer and the prediction of prognosis of gemcitabine.Methods To screen the highly deregulated microRNAs in the plasma samples of pancreatic cancer,and in the plasma samples ofpancreatic cancer patients with gemcitabine resistance using reverse transcription and quantitative PCR.Results Twenty-eight microRNAs expressing differentially with fold-exchange ＞ 2 was screened out comparing pancreatic cancer and healthy controls,and 28 microRNAs was screened out comparing gemcitabine resistant patients and gemcitabine positive patients.Conclusions There is a specific circulating mIcroRNA profile in pancreatic cancer as well as in pancreatic cancer with gemcitabine resistance.These profiles may have potential in noninvasive diagnosis of pancreatic cancer and the prediction of prognosis of gemcitabine.
Key words:
Pancreatic neoplasms ; Plasma; Circulating microRNA ; Gemcitabine; Drug resistance ; MicroRNAs
CA19-9
Cite
Citations (0)
Cite
Citations (55)
Treatment containing FOLFIRINOX was planned to be administered to a 51-year-old man with locally advanced pancreatic cancer as second-line chemotherapy and to a 66-year-old woman with recurrent pancreatic cancer as third-line chemotherapy in their treatments. Since both patients were revealed to harbor UGT1A1 polymorphisms, which were highly associated with irinotecan-induced toxicity(the former: UGT1A1 *6/*28, the latter: UGT1A1*6/*6), there was no alternative hopeful treatment other than FOLFIRINOX for them. Therefore, FOLFIRINOX was administered very carefully. Although both patients showed Grade 4 neutropenia during the initial course, it was controllable with G-CSF administration and following stepwise reduction of the irinotecan dose. Severe diarrhea and other adverse events were not observed in both cases. Since the determined regimen of FOLFIRINOX for patients with high-risk UGT1A1 polymorphisms has not been developed yet, it would be critical to accumulate and review an experience of FOLFIRINOX administration for these patients.
FOLFIRINOX
Regimen
Cite
Citations (0)