Gemcitabine (GEM) plus oxaliplatin, folinic acid, and 5-fluorouracil (FOLFOX-4) in patients with advanced gastric cancer

Correale, Pierpaolo; Fulfaro, Fabio; Marsili, Stefania; Cicero, Giuseppe; Bajardi, Eugenia; Intrivici, Chiara; Vuolo, Giuseppe; Carli, Antonio Ferdinando; Caraglia, Michele; Prete, Salvatore Del; Greco, Ettore; Gebbia, Nicola; Francini, Guido

doi:10.1007/s00280-005-1024-1

Cited by 27 publications

(19 citation statements)

References 29 publications

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“…In an Italian phase II study to gemcitabine 1000 mg/m 2 was added to FOLFOX obtaining similar results in terms of time to progression and overall survival (OS) to EOX. 30 In another phase II study, performed in elderly patients over 70, it was demonstrated that the weekly OXALF (oxaliplatin, 5-fluorouracil and folinic acid) regimen can lead to less toxicity at the expense of a lower OS, common in the elderly. Nonetheless, EOX currently remains the standard in HER2 negative GC.…”

Section: Discussionmentioning

confidence: 99%

The potential predictive role of nuclear NHERF1 expression in advanced gastric cancer patients treated with epirubicin/oxaliplatin/capecitabine first line chemotherapy

Mangia

Caldarola

Dell'Endice

et al. 2015

Cancer Biology & Therapy

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Cellular resistance in advanced gastric cancer (GC) might be related to function of multidrug resistance (MDR) proteins. The adaptor protein NHERF1 (Na C /H C exchanger regulatory factor) is an important player in cancer progression for a number of solid malignancies, even if its role to develop drug resistance remains uncertain. Herein, we aimed to analyze the potential association between NHERF1 expression and P-gp, sorcin and HIF-1a MDR-related proteins in advanced GC patients treated with epirubicin/oxaliplatin/capecitabine (EOX) chemotherapy regimen, and its relation to response. Total number of 28 untreated patients were included into the study. Expression and subcellular localization of all proteins were assessed by immunohistochemistry on formalin-fixed paraffin embedded tumor samples. We did not found significant association between NHERF1 expression and the MDR-related proteins. A trend was observed between positive cytoplasmic NHERF1 (cNHERF1) expression and negative nuclear HIF-1a (nHIF-1a) expression (68.8% versus 31.3% respectively, P D 0.054). However, cytoplasmic P-gp (cP-gp) expression was positively correlated with both cHIF-1a and sorcin expression (P D 0.011; P D 0.002, respectively). Interestingly, nuclear NHERF1 (nNHERF1) staining was statistically associated with clinical response. In detail, 66.7% of patients with high nNHERF1 expression had a disease control rate, while 84.6% of subjects with negative nuclear expression of the protein showed progressive disease (P D 0.009). Multivariate analysis confirmed a significant correlation between nNHERF1 and clinical response (OR 0.06, P D 0.019). These results suggest that nuclear NHERF1 could be related to resistance to the EOX regimen in advanced GC patients, identifying this marker as a possible independent predictive factor.

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Section: Discussionmentioning

confidence: 99%

The potential predictive role of nuclear NHERF1 expression in advanced gastric cancer patients treated with epirubicin/oxaliplatin/capecitabine first line chemotherapy

Mangia

Caldarola

Dell'Endice

et al. 2015

Cancer Biology & Therapy

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“…The GOLF combination has been already used in the treatment of advanced colon and gastric cancer patients and showed a good safety profile and highly significant anti-tumor activity. [15][16][17] In the present paper, we have evaluated the biological and biochemical effects of GOLF on human colon cancer cells in the attempt to give a mechanistic explanation to its promising clinical activity. Our data demonstrated that GEM was able to enhance the cytotoxic and the pro-apoptotic activity of the Oxali-FUFA multidrug combination in colon carcinoma cell lines in vitro.…”

Section: Discussionmentioning

confidence: 99%

“…6 The GOLF combination has also been used in the treatment of advanced colon and gastric cancer patients and shown a good safety profile and highly significant anti-tumor activity. [15][16][17] The favorable anti-tumor activity of GOLF regimen could be explained by changes of the pharmacokinetics and pharmacodinamics of both 5-FU and OXA induced by GEM (refs. 8, 9 and unpublished results).…”

Section: Introductionmentioning

confidence: 99%

Chemotherapy regimen GOLF induces apoptosis in colon cancer cells through multi-chaperone complex inactivation and increased raf-1 ubiquitin-dependent degradation

Caraglia

Marra

Budillon

et al. 2005

Cancer Biology & Therapy

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The multi-drug combination of oxaliplatin (OXA), 5-Fluorouracil (5-FU) and leucovorin (LF) is currently considered as the gold standard treatment for metastatic colorectal carcinoma. In previous studies, we have studied a chemotherapy regimen containing gemcitabine (GEM), OXA, LF, and 5-FU (named GOLF regimen) that has shown a good safety profile and highly significant anti-tumor activity. In the present study, we have investigated on the anti-tumour mechanisms of GOLF in human colon cancer HT-29 and WiDr cell lines. We have found that GOLF induced growth inhibition that was largely caused by apoptosis differently from other combinations. Moreover, the different drugs composing GOLF were highly synergistic in inducing growth inhibition. Apoptosis induced by GOLF combination was paralleled by PARP cleavage and caspase 9 and 3 activation that were not recorded in the other combinations. An about 85% decrease of the activity of Erk and Akt was found in GOLF-treated cells. These effects were likely due to decreased expression of the upstream activator Raf-1 and of Akt itself, respectively. The intracellular levels of these signalling components can be post-translationally regulated by ubiquitin-dependent degradation through proteasome. Therefore, we have evaluated the expression of some chaperone components and we have found that GOLF did not affect the expression of both heat shock protein (HSP) 90 and 27 but induced an about 90% increase of HSP70 levels suggesting the inactivation of the multi-chaperone complex. Moreover, an about 4-fold increase of the ubiquitination of Raf-1 was also found and the addition for 12 h of 10 µM proteasome inhibitor lactacystin caused an accumulation of the ubiquitinated isoforms of Raf-1. In conclusions, GOLF was a combination highly synergistic in inducing both growth inhibition and apoptosis of colon cancer cells. These effects likely occurred through the disruption of critical survival pathways and the inactivation of multi-chaperone complex. ABBREVIATIONS

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“…This could translate into a better clinical activity and possibly result in a survival benefit. Clinical phase II studies have investigated oxaliplatin-based chemotherapies for advanced gastric cancer, with results similar to those of cisplatinbased ones, and activity of these chemotherapies has also been shown in cisplatin-pretreated patients [7][8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Effectiveness and safety of oxaliplatin compared to cisplatin for advanced, unresectable gastric cancer: a systematic review and meta-analysis

Montagnani

Turrisi

Marinozzi³

et al. 2011

Gastric Cancer

107

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Background Cisplatin has been largely used in the treatment of advanced, unresectable gastric cancer, mainly in combinations with fluoropyrimidines and anthracyclines. Oxaliplatin has been shown to be at least as effective as cisplatin for this disease, but with less toxicity and a better tolerability profile, especially for older patients. We performed a systematic review of the literature to address and quantify differences in the efficacy and the safety between oxaliplatin and cisplatin for the treatment of this disease. Methods The literature was searched for randomized controlled trials (RCTs) comparing oxaliplatin to cisplatin. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to analyze dichotomous variables. Hazard ratios (HRs) for progression and death were combined with an inverse variance method based on logarithmic conversion. A fixed effect model and Mantel-Haenszel's (M-H) method were used. Heterogeneity was tested with the Q test and the I 2 value. Sensitivity analyses were performed. Results Three RCTs were identified, involving a total of 1294 patients. Oxaliplatin significantly improved progression-free survival (HR = 0.88, p = 0.02) and overall survival (HR = 0.88, p = 0.04). Moreover, it was associated with less neutropenia (OR = 0.53, p \ 0.01) and fewer thromboembolic events (OR = 0.42, p \ 0.01), but it was also associated with increased neurotoxicity (OR = 6.91, p \ 0.01). Conclusions Our results support the existence of a small but significant survival benefit of oxaliplatin over cisplatin. Oxaliplatin is associated with less toxicity and better tolerability, especially in older patients and when used in twodrug, bi-weekly regimens.

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Gemcitabine (GEM) plus oxaliplatin, folinic acid, and 5-fluorouracil (FOLFOX-4) in patients with advanced gastric cancer

Abstract: these results may grant the rationale to evaluate this multi-drug combination in randomized phase III trials in advanced gastric cancer.

Cited by 27 publications

References 29 publications

The potential predictive role of nuclear NHERF1 expression in advanced gastric cancer patients treated with epirubicin/oxaliplatin/capecitabine first line chemotherapy

The potential predictive role of nuclear NHERF1 expression in advanced gastric cancer patients treated with epirubicin/oxaliplatin/capecitabine first line chemotherapy

Chemotherapy regimen GOLF induces apoptosis in colon cancer cells through multi-chaperone complex inactivation and increased raf-1 ubiquitin-dependent degradation

Effectiveness and safety of oxaliplatin compared to cisplatin for advanced, unresectable gastric cancer: a systematic review and meta-analysis

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