Genetic polymorphism in ATIC is associated with effectiveness and toxicity of pemetrexed in non-small-cell lung cancer

Thorax ◽  
2021 ◽  
pp. thoraxjnl-2020-216504
Author(s):  
Sabine Visser ◽  
Stijn Koolen ◽  
Nadine van Donk ◽  
Nico van Walree ◽  
Cor van der Leest ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Treatment Effectiveness ◽  
Small Cell ◽  
Disease Stage ◽  
Severe Neutropenia ◽  
Small Cell Lung ◽  
Folate Pathway ◽  
Multicentre Cohort Study

Patients with advanced non-small-cell lung cancer who are treated with pemetrexed display a wide variation in clinical response and toxicity. In this prospective, multicentre cohort study, we investigated the association with treatment effectiveness and toxicity of 10 polymorphisms in nine candidate genes, covering the folate pathway (MTHFR), cell transport (SLC19A1/ABCC2/ABCC4), intracellular metabolism (FPGS/GGH) and target enzymes (TYMS/DHFR/ATIC) of pemetrexed. Adjusted for sex, ECOG performance score and disease stage, the association between ATIC (rs12995526) and overall survival (HR 1.59, 95% CI 1.06 to 2.39) was significant. Regarding toxicity, this ATIC polymorphism was significantly associated with severe laboratory (p=0.014) and clinical (p=0.016) chemotherapy-related adverse events, severe neutropenia (p=0.007) and all-grade diarrhoea (p=0.034) in multivariable analyses.

Prognostic value of Platelet-to-Lymphocyte Ratio (PLR) and IL-6 in patients with small cell lung cancer

2018 ◽  
Vol 54 (3) ◽  
pp. 137-144
Author(s):  
Ewa Wójcik ◽  
Zofia Stasik ◽  
Urszula Rychlik ◽  
Jadwiga Tarapacz ◽  
Jan Kanty Kulpa ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Tumour Marker ◽  
Small Cell ◽  
Disease Stage ◽  
Small Cell Lung ◽  
Platelet To Lymphocyte Ratio ◽  
Lymphocyte Ratio ◽  
Favourable Prognosis

Background: In order to identify patients with the most favourable prognosis, the effect of baseline level of interleukin-6 (IL-6) and platelet-to-lymphocyte ratio (PLR) on survival was analysed in patients with small cell lung cancer.<br>Material and Methods: 159 patients with small cell lung cancer were enrolled. Full blood count enabling computing the PLR, as well as NSE, ProGRP and IL-6 levels were done in all participants.<br>Results: We demonstrated significant effect of disease stage, performance status, sex, initial NSE, ProGRP and IL-6 levels as well as PLR on survival of patients with SCLC. In subgroups with normal initial levels of ProGRP (below 50.36 ng/L) and NSE (below 20.95 μg/L), the IL-6 level above 6.0 ng/L worsens the prognosis by 28% and 29%, respectively. In a subgroup with elevated initial ProGRP, the difference in survival between patients with normal vs elevated IL-6 level at baseline was 25%, whereas in a subgroup with elevated initial NSE it was 14%. The between-subgroup differences in PLR were less considerable. There was a significant effect of PLR on patient survival in a subgroup with normal initial NSE level and elevated initial ProGRP level.<br>Conclusion: In subgroups of SCLC patients identified based on initial tumour marker levels, IL-6 level can be a source of reliable prognostic information, whereas the effect of PLR is less marked. Patients with normal tumour marker levels and IL-6 below 6 ng/L at baseline have the most favourable prognosis.

Early alternating chemotherapy and radiotherapy schedule in limited disease stage small cell lung cancer

1995 ◽  
Vol 31 (9) ◽  
pp. 1434-1436 ◽  
Author(s):  
A. Purohit ◽  
A. Charloux ◽  
G.-M. Jung ◽  
A. Dietemann ◽  
P. Fraisse ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Disease Stage ◽  
Small Cell Lung ◽  
Limited Disease ◽  
Alternating Chemotherapy

scholarly journals Successful Management of Crizotinib-Induced Neutropenia in a Patient with Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer: A Case Report

2016 ◽  
Vol 9 (1) ◽  
pp. 51-55 ◽  
Author(s):  
Jun Osugi ◽  
Yuki Owada ◽  
Takumi Yamaura ◽  
Satoshi Muto ◽  
Naoyuki Okabe ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Dose Reduction ◽  
Cell Lung Cancer ◽  
Anaplastic Lymphoma Kinase ◽  
Small Cell ◽  
Severe Neutropenia ◽  
Small Cell Lung ◽  
Successful Management ◽  
Anaplastic Lymphoma

Crizotinib, the first clinically available inhibitor of anaplastic lymphoma kinase (ALK) gene rearrangement, is generally well tolerated. In contrast, neutropenia induced by crizotinib is a commonly reported grade 3 or 4 adverse event. In such cases, interruption and dose reduction of crizotinib might be necessary for some patients with severe neutropenia. However, information concerning clinical experience and management of severe neutropenia is currently limited. In this report, the successful management of crizotinib-induced neutropenia by dose reduction of crizotinib in a patient with ALK-positive non-small cell lung cancer is described.

Phase I trial of escalating doses of ABI-007 (nanoparticle albumin-bound paclitaxel) and gemcitabine in patients (pts) with thoracic malignancies

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 18094-18094
Author(s):  
C. B. Lee ◽  
T. E. Stinchcombe ◽  
M. A. Socinski ◽  
D. N. Hayes ◽  
R. M. Goldberg ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Febrile Neutropenia ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Severe Neutropenia ◽  
Hematologic Toxicity ◽  
Small Cell Lung ◽  
Grade 3 ◽  
Thoracic Malignancies

18094 Background: ABI-007, nanoparticle albumin-bound paclitaxel, has a different toxicity profile than solvent-based paclitaxel including a lower rate of severe neutropenia. This trial was designed to determine the maximum tolerated dose (MTD) of ABI-007 in combination with gemcitabine (G) in patients with thoracic malignancies. Methods: Patients were required to have a performance status of 0–1, =3 cytotoxic chemotherapy regimens, and preserved renal, hepatic, and bone marrow function. Patients received G 1,000 mg/m2 on days 1, 8 in all cohorts and ABI-007 on day 1 at doses of 260, 300, 340 mg/m2 depending on the treatment cohort every 21 days (1 cycle = 21 days). Day 8 G dose modifications were: G held for ANC < 500 x 109/L or platelets (plts) < 50,000 x 109/L, and 75% of the G dose was given if the ANC 500–999 x 109/L or plts 50,000–99,000 x 109/L. Dose limiting toxicities (DLT) were assessed after the first cycle and were defined as: grade 3 non-hematologic toxicity, febrile neutropenia, grade 4 anemia or thrombocytopenia, ANC = 500 for = 7 days, 2-week delay in initiating the second cycle, or omission of the day 8 G. Doses were escalated in cohorts of 3–6 pts. Results: Thirteen patients were consented and 12 pts were treated (median age 62.5 years (range 35–75); median number of prior treatments 2.5 (range 1–4); tumor types: 6 non-small cell lung cancer (NSCLC), 5 small cell lung cancer (SCLC), and 1 esophageal. At an ABI-007 dose of 300 mg/m2, 1 of 6 pts experienced a DLT (omission of day 8 G due to ANC < 500), and at an ABI-007 dose of 340 mg/m2 2 of 3 patients experienced a DLT (1 pt grade 3 rash and pruritus; 1 pt grade 3 fatigue and anorexia). Additional grade 3 or 4 toxicities observed over all cycles were: neutropenia (n=2), sensory neuropathy (n=1), febrile neutropenia (n=1). G was given at full dose in 38 of the 39 cycles. Eight pts were evaluable for response by RECIST: 4 partial responses (SCLC, n=2; NSCLC, n=2), 4 stable disease (NSCLC, n=3; esophageal, n=1). Conclusions: The MTD of ABI-007 is 300 mg/m2 day 1 in combination with G 1,000 mg/m2 on days 1, 8 every 21 days. This combination was well tolerated and demonstrated activity in previously treated NSCLC and SCLC patients. No significant financial relationships to disclose.

Exploring sex differences in small cell lung cancer: Is this a hormonal issue?

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e20077-e20077
Author(s):  
Narjust Duma ◽  
Thanh P. Ho ◽  
Urshila Durani ◽  
Shealeigh Funni ◽  
Jonathan Inselman ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Menopausal Status ◽  
Multivariable Analysis ◽  
Older Men ◽  
Small Cell ◽  
Disease Stage ◽  
Small Cell Lung ◽  
Menopausal Women

e20077 Background: Small cell lung cancer (SCLC) accounts for about 10% to 15% of lung cancers among women and men. Though heavily associated with smoking, its incidence in women is rapidly increasing despite a decline in cigarette exposure. Given the changing demographics of SCLC and hormonal factors associated with other forms of lung cancer, we studied differences between sexes in SCLC. Methods: Utilizing the National Cancer Database, we identified all incident SCLC cases from 2004 to 2014. Patients were classified as limited stage (LS) or extensive stage (ES). Women were stratified by menopausal status (≥55 years = postmenopausal). Kaplan-Meier method and Cox regression were used for overall survival (OS) and multivariable analysis. Results: 161,978 patients were identified. No significant sociodemographic differences were observed between sexes. The majority of patients were non-Hispanic whites (89.1%), followed by non-Hispanic blacks (7.5%). Men were more likely to be diagnosed with ES disease than women (63% vs. 56%). Both sexes initiated treatment within a similar time frame from diagnosis (chemotherapy, median: 18 days, IQR 8-32). Women had better median OS compared to men in both LS (15.2 vs. 12.7 months, HR: 0.85, 95% CI 0.83-0.86, p < 0.0001) and ES (6.4 vs. 5.7 months, HR: 0.88, 95% CI 0.87-0.90, p < 0.0001). No racial or ethnic disparities in OS were observed, overall and when examined within sex and disease stage groups. Differences between sexes in OS were also observed when comparing patients within the same racial/ethnic group (women having better OS). When divided by menopausal status, postmenopausal women with LS and ES had worse OS than premenopausal women (14.7 vs. 22 months, HR: 1.50, 95% CI 1.44-1.56; 6.1 vs. 9.8 months, HR: 1.41, 95% CI: 1.37-1.46, respectively). We also observed worse OS in older men when divided by age ( < 55 years and ≥55 years). In multivariable analysis, older age, postmenopausal status, and Medicaid as primary insurance were associated with worse OS for both LS and ES. Conclusions: In this large cohort, women with SCLC had better OS compared to men. Post-menopausal women had worse OS compared to pre-menopausal women. Since older men had a similar trend of worse survival compared to younger men, age might exert a more significant influence on survival than hormonal status in SCLC. Further studies with data on sexual hormone levels are necessary to better understand their role in women with SCLC.

Randomized Phase III Study of Surgery Alone or Surgery Plus Preoperative Cisplatin and Gemcitabine in Stages IB to IIIA Non–Small-Cell Lung Cancer

2012 ◽  
Vol 30 (2) ◽  
pp. 172-178 ◽  
Author(s):  
Giorgio V. Scagliotti ◽  
Ugo Pastorino ◽  
Johan F. Vansteenkiste ◽  
Lorenzo Spaggiari ◽  
Francesco Facciolo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Radical Surgery ◽  
Small Cell ◽  
Phase Iii ◽  
Disease Stage ◽  
Chemotherapy Response ◽  
Small Cell Lung ◽  
Stage Ib

PurposeThis study aimed to determine whether three preoperative cycles of gemcitabine plus cisplatin followed by radical surgery provides a reduction in the risk of progression compared with surgery alone in patients with stages IB to IIIA non–small-cell lung cancer (NSCLC).Patients and MethodsPatients with chemotherapy-naive NSCLC (stages IB, II, or IIIA) were randomly assigned to receive either three cycles of gemcitabine 1,250 mg/m2days 1 and 8 every 3 weeks plus cisplatin 75 mg/m2day 1 every 3 weeks followed by surgery, or surgery alone. Randomization was stratified by center and disease stage (IB/IIA v IIB/IIIA). The primary end point was progression-free survival (PFS).ResultsThe study was prematurely closed after the random assignment of 270 patients: 129 to chemotherapy plus surgery and 141 to surgery alone. Median age was 61.8 years and 83.3% were male. Slightly more patients in the surgery alone arm had disease stage IB/IIA (55.3% v 48.8%). The chemotherapy response rate was 35.4%. The hazard ratios for PFS and overall survival were 0.70 (95% CI, 0.50 to 0.97; P = .003) and 0.63 (95% CI, 0.43 to 0.92; P = .02), respectively, both in favor of chemotherapy plus surgery. A statistically significant impact of preoperative chemotherapy on outcomes was observed in the stage IIB/IIIA subgroup (3-year PFS rate: 36.1% v 55.4%; P = .002). The most common grade 3 or 4 chemotherapy-related adverse events were neutropenia and thrombocytopenia. No treatment-by-histology interaction effect was apparent.ConclusionAlthough the study was terminated early, preoperative gemcitabine plus cisplatin followed by radical surgery improved survival in patients with clinical stage IIB/IIIA NSCLC.

Expression of Periostin in Patients with Non-Small Cell Lung Cancer: Correlation with Angiogenesis and Lymphangiogenesis

2008 ◽  
Vol 23 (3) ◽  
pp. 182-186 ◽  
Author(s):  
I. Takanami ◽  
T. Abiko ◽  
S. Koizumi
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Microvessel Density ◽  
Survival Rates ◽  
Additive Model ◽  
Small Cell ◽  
Disease Stage ◽  
Small Cell Lung ◽  
Lymphatic Microvessel Density

The aim of this study was to evaluate periostin expression measured immunohistochemically in patients with non-small cell lung cancer (NSCLC) and to determine its association with clinical features, prognosis, angiogenesis, and lymphangiogenesis. We investigated periostin expression in a series of 88 patients with NSCLC. We also determined whether expression of periostin correlated with microvessel density and lymphatic microvessel density. Periostin was expressed in 42% of 88 patients. Its expression was significantly correlated with tumor size, lymph node metastasis, disease stage, and lymphatic invasion (p=0.0128, 0.0015, 0.0310 and 0.0273, respectively). There also was a significant relation between periostin expression and microvessel density and lymphatic microvessel density (all p<0.0001). Five-year survival rates were better in patients with negative periostin expression than in those with positive periostin expression (p=0.0044). Periostin expression was not significant in a multivariate additive model. Our findings show that periostin correlates with increased tumor progression and a worse prognosis in NSCLC, as well as with angiogenesis and lymphangiogenesis.

Paclitaxel and carboplatin in combination in the treatment of advanced non-small-cell lung cancer: a phase II toxicity, response, and survival analysis.

1995 ◽  
Vol 13 (8) ◽  
pp. 1860-1870 ◽  
Author(s):  
C J Langer ◽  
J C Leighton ◽  
R L Comis ◽  
P J O'Dwyer ◽  
C A McAleer ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Survival Time ◽  
Cell Lung Cancer ◽  
Stage Iv ◽  
Small Cell ◽  
Phase Iii ◽  
Disease Stage ◽  
Small Cell Lung ◽  
Grade 3

PURPOSE To determine the activity and toxicity of combination paclitaxel (24 hours) and carboplatin in advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Eligibility required measurable disease (stage IV or stage IIIB with malignant pleural effusion), Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, absolute neutrophil count > or = 2,000/microL, platelet count > or = 100,000/microL serum creatinine concentration < or = 1.5 mg/dL, and bilirubin level < or = 2 mg/dL. Paclitaxel was initially administered at a dose of 135 mg/m2/d, followed by carboplatin on day 2 at a targeted area under the concentration-time curve (AUC) of 7.5 using the Calvert formula. Granulocyte colony-stimulating factor (G-CSF) 5 micrograms/kg subcutaneously (SC) on days 3 to 17 was introduced during the second and subsequent cycles. In patients who sustained less than grade 4 myelosuppression, the paclitaxel dose was sequentially escalated 40 mg/m2 per cycle to a maximum of 215 mg/m2. Treatment was repeated at 3-week intervals for six cycles. RESULTS From June 1993 through February 1994, 54 patients were enrolled; 53 are assessable for toxicity and response. The median age was 62 years (range, 34 to 84). Sixty-nine percent were male, 65% had adenocarcinoma, and 93% had stage IV disease. Two hundred sixty-eight cycles were administered; 32 patients (59%) completed all six cycles. Twenty-five unanticipated hospitalizations occurred during treatment (9.3% of cycles) in 20 patients (37%). Myelosuppression was the principal toxicity; grade 3 or 4 granulocytopenia occurred in 57% of patients after the first cycle, but decreased to 35% during the second cycle after introduction of G-CSF and consistently remained < or = 22% during subsequent cycles. Seven episodes of neutropenic fever occurred, all during the first cycle. Grade 3 or 4 thrombocytopenia and anemia occurred in 47% and 33% of patients, respectively. Eight patients (15%) required platelet transfusions and 16 (30%) required packed RBC support. Neuropathy, myalgias/arthralgias, and thrombocytopenia, although generally mild, were cumulative. The paclitaxel dose was boosted to 215 mg/m2 in > or = 70% of patients who received three or more cycles. At an AUC of 7.5, the median first-cycle carboplatin dose was 424 mg/m2 (range, 273 to 709 mg/m2). The objective response rate was 62%, with five (9%) complete responses and 28 (53%) partial responses. The median progression-free survival time was 28 weeks and the median survival time 53 weeks. The 1-year survival rate is 54%. CONCLUSION The paclitaxel-carboplatin combination is active in advanced NSCLC and may enhance survival; it merits further investigation in phase III trials.

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