Active Smoking May Negatively Affect Response Rate, Progression-Free Survival, and Overall Survival of Patients With Metastatic Renal Cell Carcinoma Treated With Sunitinib

Keizman, Daniel; Gottfried, Maya; Ish‐Shalom, Maya; Maimon, Natalie; Peer, Avivit; Neumann, Avivit; Hammers, Hans J.; Eisenberger, Mario A.; Sinibaldi, Victoria J.; Пили, Роберто; Hayat, Henry; Kovel, Svetlana; Sella, Avishay; Boursi, Ben; Weitzen, Rony; Mermershtain, Wilmosh; Rouvinov, Keren; Berger, Raanan; Carducci, Michael A.

doi:10.1634/theoncologist.2012-0335

Cited by 59 publications

(47 citation statements)

References 35 publications

(62 reference statements)

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“…All trials were conducted in adult patients. Eight studies were conducted in Asian countries, including three in Turkey [11, 12, 14], two in China [17, 19], two in Israel [13, 15] and one in Korea [16]. The single remaining study was conducted in Italy [18].…”

Section: Resultsmentioning

confidence: 99%

“…Heterogeneity is illustrated in each forest plot. In Figure 2, OS values were available from eight [11–13, 15–19] studies on renal cell carcinoma. The synthesized hazard risk favored the low NLR patients (pooled HR: 1.93, 95% CI: 1.35-2.77; P = 0.0003; I 2 = 82%), which meant that patients with a higher NLR had a greater mortality risk than those with a low NLR.…”

Section: Resultsmentioning

confidence: 99%

“…The synthesized hazard risk favored the low NLR patients (pooled HR: 1.93, 95% CI: 1.35-2.77; P = 0.0003; I 2 = 82%), which meant that patients with a higher NLR had a greater mortality risk than those with a low NLR. Figure 3 shows that eight [11–15, 17–19] studies provided sufficient data on PFS outcome. The pooled results showed significant superiority of a low NLR in renal cancer (pooled HR: 2.12, 95% CI: 1.42–3.17; P = 0.0002; I 2 = 88%).…”

Section: Resultsmentioning

confidence: 99%

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Meta-analysis of the efficacy of the pretreatment neutrophil-to-lymphocyte ratio as a predictor of prognosis in renal carcinoma patients receiving tyrosine kinase inhibitors

Yao

Cheng

et al. 2016

Oncotarget

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The data on the impact of the neutrophil-to-lymphocyte ratio (NLR) in metastatic renal cell carcinoma (mRCC) patients receiving tyrosine kinase inhibitors (TKIs) are inconsistent. We therefore performed a meta-analysis to assess the prognostic value of pretreatment NLR in patients treated with TKIs for mRCC. We searched the Embase, Medline, PubMed, Cochrane and ISI Web of Knowledge to identify clinical studies that had evaluated the association between the pretreatment NLR and prognosis in mRCC patients. Prognostic outcomes included overall survival (OS) and progression-free survival (PFS). Nine studies encompassing a total of 1091 participants were included. We found that a high NLR was an effective prognostic marker of both OS (pooled HR: 1.93, 95% CI: 1.35-2.77; P = 0.0003) and PFS (pooled HR: 2.12, 95% CI: 1.42-3.17; P = 0.0002). Subgroup analysis revealed that studies reporting a NLR ≥ 3 showed a more significant effect of NLR on both OS (pooled HR: 2.50, 95% CI: 1.99-3.14; P = 0.0003) and PFS (pooled HR: 2.17, 95% CI: 1.26-3.75). This meta-analysis suggests that high pretreatment NLR is associated with a poor prognosis in mRCC patients receiving TKI treatment.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Meta-analysis of the efficacy of the pretreatment neutrophil-to-lymphocyte ratio as a predictor of prognosis in renal carcinoma patients receiving tyrosine kinase inhibitors

Yao

Cheng

et al. 2016

Oncotarget

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“…10,11,37,39–44 Other factors such as cigarette smoking, gender, body weight, and age have also been associated with sunitinib toxicity and treatment outcomes. 33,42,43,45–47 Individualization of sunitinib treatment based on genetic and nongenetic factors has been proposed to help improve sunitinib efficacy and reduce toxicity. 10,48,49 …”

Section: Discussionmentioning

confidence: 99%

Cytochromes P450 1A2 and 3A4 Catalyze the Metabolic Activation of Sunitinib

Amaya

Durandis

Bourgeois

et al. 2018

Chem. Res. Toxicol.

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Sunitinib is a multitargeted tyrosine kinase inhibitor associated with idiosyncratic hepatotoxicity. The mechanisms of this toxicity are unknown. We hypothesized that sunitinib undergoes metabolic activation to form chemically reactive, potentially toxic metabolites which may contribute to development of sunitinib-induced hepatotoxicity. The purpose of this study was to define the role of cytochrome P450 (P450) enzymes in sunitinib bioactivation. Metabolic incubations were performed using individual recombinant P450s, human liver microsomal fractions, and P450-selective chemical inhibitors. Glutathione (GSH) and dansylated GSH were used as trapping agents to detect reactive metabolite formation. Sunitinib metabolites were analyzed by liquid chromatography–tandem mass spectrometry. A putative quinoneimine–GSH conjugate (M5) of sunitinib was detected from trapping studies with GSH and dansyl–GSH in human liver microsomal incubations, and M5 was formed in an NADPH-dependent manner. Recombinant P450 1A2 generated the highest levels of defluorinated sunitinib (M3) and M5, with less formation by P450 3A4 and 2D6. P450 3A4 was the major enzyme forming the primary active metabolite N-desethylsunitinib (M1). In human liver microsomal incubations, P450 3A inhibitor ketoconazole reduced formation of M1 by 88%, while P450 1A2 inhibitor furafylline decreased generation of M5 by 62% compared to control levels. P450 2D6 and P450 3A inhibition also decreased M5 by 54 and 52%, respectively, compared to control. In kinetic assays, recombinant P450 1A2 showed greater efficiency for generation of M3 and M5 compared to that of P450 3A4 and 2D6. Moreover, M5 formation was 2.7-fold more efficient in human liver microsomal preparations from an individual donor with high P450 1A2 activity compared to a donor with low P450 1A2 activity. Collectively, these data suggest that P450 1A2 and 3A4 contribute to oxidative defluorination of sunitinib to generate a reactive, potentially toxic quinoneimine. Factors that alter P450 1A2 and 3A activity may affect patient risk for sunitinib toxicity.

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“…Thus, diagnosis could present a 'teachable moment' when patients are receptive to smoking cessation interventions, particularly older patients with advanced disease [38]. In addition, the 'teachable moment' might be relevant to patients with other types of tumour where active smoking during treatment may also be detrimental in their situation [39].…”

Section: Discussionmentioning

confidence: 99%

The relationship between smoking and quality of life in advanced lung cancer patients: a prospective longitudinal study

Danson

Rowland

Rowe

et al. 2015

Support Care Cancer

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PurposeSmoking is a major cause of lung cancer and continued smoking may compromise treatment efficacy and quality of life (HRQoL) in patients with advanced lung cancer.Our aims were to determine i) preference for treatments which promote quality over length of life depending on smoking status, ii) the relationship between HRQoL and smoking status at diagnosis (T1), after controlling for demographic and clinical variables and iii) changes in HRQoL 6 months after diagnosis (T2) depending on smoking status. Methods296 patients with advanced lung cancer were given questionnaires to assess HRQoL (EORTC-QLQ-C30), time-trade off for life quality versus quantity (QQQ) and smoking history (current, former or never smoker) at diagnosis (T1) and six months later (T2). Medical data were extracted from case records. ResultsQuestionnaires were returned by 202 (68.2%) patients at T1 and 114 (53.3%) at T2.Patients favoured treatments that would enhance quality of life over increased longevity. Those who continued smoking after diagnosis reported worse HRQoL than former smokers or those who never smoked. Smoking status was a significant independent predictor of coughing in T1 (worse in smokers), and Cognitive Functioning in T2 (better in never-smokers).3 ConclusionsSmoking by patients with advanced lung cancer is associated with worse symptoms on diagnosis and poorer HRQoL for those who continue smoking. The results have implications to help staff explain the consequences of smoking to patients.

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Active Smoking May Negatively Affect Response Rate, Progression-Free Survival, and Overall Survival of Patients With Metastatic Renal Cell Carcinoma Treated With Sunitinib

Cited by 59 publications

References 35 publications

Meta-analysis of the efficacy of the pretreatment neutrophil-to-lymphocyte ratio as a predictor of prognosis in renal carcinoma patients receiving tyrosine kinase inhibitors

Meta-analysis of the efficacy of the pretreatment neutrophil-to-lymphocyte ratio as a predictor of prognosis in renal carcinoma patients receiving tyrosine kinase inhibitors

Cytochromes P450 1A2 and 3A4 Catalyze the Metabolic Activation of Sunitinib

The relationship between smoking and quality of life in advanced lung cancer patients: a prospective longitudinal study

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