Final results from a Phase II study of pemetrexed and cisplatin with concurrent thoracic radiation after Pem-Cis induction in patients with unresectable locally advanced non-squamous non-small cell lung cancer (NSCLC)

Garrido, Pilar; Engel-Riedel, Walburga; Serke, Monika; Giraud, P.; Ricardi, Umberto; Vallejo, Carmen; Visseren‐Grul, Carla; Ameryckx, Sophie; Soldatenkova, Victoria; Chouaki, N.; Novello, Silvia

doi:10.1016/j.lungcan.2015.02.014

Cited by 12 publications

(8 citation statements)

References 21 publications

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“…These data align with results from the overall study population,3 suggesting that this regimen is feasible in elderly and non-elderly patients alike and may help in making the disease surgically resectable in elderly patients with good performance. Findings should be interpreted with caution due to the exploratory nature and small number of elderly patients included.…”

supporting

confidence: 83%

“…In a phase II study, treatment with two cycles of pemetrexed-cisplatin (Pem-Cis) induction, followed by full-dose Pem-Cis plus concurrent RT was well tolerated and effective in 90 patients with stage IIIA/IIIB unresectable, non-squamous NSCLC 3. Here, we report by-age subgroup data for 17 elderly (aged >70 years) and 73 non-elderly patients (aged ≤70 years).…”

mentioning

confidence: 97%

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Pemetrexed-cisplatin with concurrent thoracic radiation after pemetrexed-cisplatin induction in patients with unresectable locally advanced non-squamous NSCLC: results by age subgroup

et al. 2017

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confidence: 83%

mentioning

confidence: 97%

Pemetrexed-cisplatin with concurrent thoracic radiation after pemetrexed-cisplatin induction in patients with unresectable locally advanced non-squamous NSCLC: results by age subgroup

et al. 2017

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“…Cisplatin is the first drug approved for clinical use for cancer chemotherapy [22]. It has become evident that cisplatin-based chemotherapy could improve the prognosis of patients and prolong survival of patients with various cancer types including non-small cell lung cancer [23, 24]. Currently, cisplatin-based chemotherapy is an accepted standard of care for systemic therapy for patients at advanced stages of NSCLC [23, 24].…”

Section: Discussionmentioning

confidence: 99%

Glutathione Peroxidase 1 Promotes NSCLC Resistance to Cisplatin via ROS-Induced Activation of PI3K/AKT Pathway

Chen

Shen

et al. 2019

BioMed Research International

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Purpose. Reactive oxygen species (ROS)-induced cytotoxicity is an important mechanism by which cisplatin kills tumor cells. Glutathione peroxidase family (GPXs) is an important member of antioxidant system which metabolizes intracellular ROS and maintains homeostasis of cells. Altered expressions of GPXs enzymes, especially GPX1, have been described in a variety of human cancers. However, their functional roles in cisplatin-based chemoresistance in human malignancies including non-small cell lung cancer have never been explored. Methods. A panel of NSCLC cell lines were selected for this study. GPX1 expression was detected using quantitative RT-PCR and Western blot. Cisplatin-induced cell killing was analyzed by CCK8 assay. Intracellular ROS levels were detected by fluorescence-based flow cytometry analysis. In vitro overexpression and knockdown of GPX1 expression were performed using GPX1 expression vector and siRNA approaches. Protein levels of PTEN, NF-κB, BCL2, Bax, and phosphorylated AKT were detected with western blot analysis using specific antibodies. Results. GPX1 expression was upregulated in a subset of NSCLC cell lines resistant to cisplatin treatment. Expression vector-mediated forced overexpression of GPX1 significantly increased cisplatin resistance in NSCLC cell lines, whereas RNA inference-mediated downregulation of GPX1 could restore sensitivity to cisplatin. Overexpression of GPX1 significantly suppressed elevation of intracellular ROS and activation of AKT pathway when NSCLC cell lines were exposed to different concentrations of cisplatin. Activation of the AKT pathway inhibited proapoptotic cascade and subsequently led to cisplatin resistance in NSCLC cells. Inhibition of NF-κB by its chemical inhibitor BAY can significantly downregulate GPX1 expression and restore the cisplatin sensitivity of the cell lines resistant to cisplatin. Conclusions. Our findings suggested that overexpression of GPX1 is a novel molecular mechanism for cisplatin-based chemoresistance in NSCLC. GPX1 overexpression blocks cisplatin-induced ROS intracellular accumulation, activates PI3K-AKT pathway by increased AKT phosphorylation, and further leads to cisplatin resistance in NSCLC cells. Inhibition of NF-κB signaling may be an alternative approach for restoring cisplatin sensitivity for NSCLC cells resistant to cisplatin-based chemotherapy.

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“…A phase I study of pemetrexed plus cisplatin followed by pemetrexed consolidation therapy with dose-escalation of TRT in patients with locally advanced nonsquamous NSCLC showed that the objective response rate was 83 %. A phase II study of pemetrexed plus cisplatin with concurrent TRT in Stage IIIA or Stage IIIB non-squamous NSCLC showed a best overall response of 72 %(PFS, 13.8 months; OS, 26.2 months) [ 43 ]. Furthermore, a randomized phase III study was performed to investigate the effect of pemetrexed 500 mg/m 2 + cisplatin 75 mg/m 2 or etoposide 50 mg/m 2 + cisplatin 50 mg/m 2 with plus concurrent TRT followed by pemetrexed consolidation cytotoxic chemotherapy in locally advanced nonsquamous NSCLC [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

A phase I study of nedaplatin, pemetrexed and thoracic intensity-modulated radiotherapy for inoperable stage III lung adenocarcinoma

Deng

et al. 2016

BMC Cancer

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BackgroundConcurrent chemotherapy and radiation is the standard treatment for unresectable stage III Lung adenocarcinoma. However, no optimal concurrent chemotherapeutic regimen has been described. This study aimed to assess concurrent pemetrexed, nedaplatin and thoracic intensity-modulated radiotherapy followed by consolidation pemetrexed/nedaplatin for unresectable Stage IIIA/B lung adenocarcinoma.MethodsPatients with unresectable stage III lung adenocarcinoma received thoracic intensity-modulated radiotherapy at 60–64 Gy in 30–32 fractions, concurrently with two cycles of 500 mg/m2 pemetrexed, with nedaplatin doses escalating from 60 mg/m2 (level 1) to 70 mg/m2 (level 2) and 80 mg/m2 (level 3). Consolidation consisted of three pemetrexed/nedaplatin (500 mg/m2, 60 mg/m2) cycles every 3 weeks after concurrent therapy. The primary objective of the safety was to determine the maximum-tolerated dose (MTD). The secondary endpoints included response rate, PFS and OS.ResultsFifteen patients were enrolled, including 3, 6 and 6 individuals in the first, second, and third dose levels, respectively. Three cases of dose-limiting toxicities (grade 3 hepatitis, pneumonitis, and grade 4 thrombocytopenia), including one and two patients at levels 2 and 3, respectively, were observed and resulted in discontinued/delayed treatment. Response rates were 86.7 % (95 % confidence interval [CI], 64.2–97.8 %) and 64.3 % (95 % CI, 38.3–85.4 %) at chemoradiation and treatment completions, respectively. Median OS was 30.0 months (95 % CI, 16.4–43.6 months); 2-year OS was 44.0 % (95 % CI, 18.7–69.2 %). Median PFS was 12.0 months (95 % CI, 6.9–17.0 months), and the 2-year PFS 27.0 % (95 % CI, 4.7–49.3 %).ConclusionsFull dose 500 mg/m2 of pemetrexed and nedaplatin 70 mg/m2 could be used safely with thoracic intensity-modulated radiotherapy for inoperable stage III lung adenocarcinoma. Further evaluation of stage III lung adenocarcinoma management is warranted.Trial registrationThis study was retrospectively registered at Chinese Clinical Trial Registry (ChiCTR-OPN-16008316, April 2016).

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Final results from a Phase II study of pemetrexed and cisplatin with concurrent thoracic radiation after Pem-Cis induction in patients with unresectable locally advanced non-squamous non-small cell lung cancer (NSCLC)

Abstract: In this study of Pem-Cis induction CT followed by full-dose Pem-Cis with concurrent RT, median PFS was 10.6 months and toxicity was manageable, in line with previous data on Pem-Cis plus RT.

Cited by 12 publications

References 21 publications

Pemetrexed-cisplatin with concurrent thoracic radiation after pemetrexed-cisplatin induction in patients with unresectable locally advanced non-squamous NSCLC: results by age subgroup

Pemetrexed-cisplatin with concurrent thoracic radiation after pemetrexed-cisplatin induction in patients with unresectable locally advanced non-squamous NSCLC: results by age subgroup

Glutathione Peroxidase 1 Promotes NSCLC Resistance to Cisplatin via ROS-Induced Activation of PI3K/AKT Pathway

A phase I study of nedaplatin, pemetrexed and thoracic intensity-modulated radiotherapy for inoperable stage III lung adenocarcinoma

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