ABSTRACT: First-line platinum-based chemotherapy is currently considered the standard treatment for unresectable non-small cell lung cancer (NSCLC). However, resistance to platinum-based chemotherapy results in poor prognoses. The DNA repair pathway is a crucial molecular mechanism potentially involved in resistance to platinum-based chemotherapy. ERCC2 plays an integral role in the nucleotide excision repair pathway. Furthermore, single nucleotide polymorphisms (SNPs) and haplotypes in the ERCC2 gene are thought to be associated with the risk of developing lung cancer and clinical outcomes. Therefore, we evaluated the impact of ERCC2 haplotype-tagging SNPs (htSNPs) on the clinical parameters of first-line platinum-based chemotherapy in unresectable NSCLC.
We genotyped 8 ERCC2 htSNPs for 129 unresectable NSCLC (stage IIIA, 12; stage III, 36; stage IV, 82) cases treated with first-line platinum-based chemotherapy. Clinical characteristics, treatment outcomes, hematological and non-hematological toxicities, and predictive value of the htSNPs in patient response, survival, and adverse events related to platinum-based chemotherapy were analyzed according to each ERCC2 htSNP using the chi-square test, Kaplan-Meier method, and Cox proportional hazard model.
No differences were observed in patient or disease characteristics and response according to ERCC2 htSNPs. In a survival analysis, rs50872 was significantly related to overall survival (OS) (log-rank test, p=0.014). The median survival duration of rs50872 G/G, A/G, and A/A genotypes was 35.75 (95% confidence interval [CI] 21.05-50.45), 36.07 (hazard ratio [HR] 1.02, 95% CI 25.20-46.94), and 16.75 (HR 3.49, 95% CI 5.73-27.77) months, respectively. A significant association was observed between grades 3 and 4 infections and poor survival: OS in patients with a grade 0-2 infection: 35.75 months (95% CI 28.15-43.35); OS in patients with a grade 3-4 infection: 12.86 months (95% CI 8.99-16.72, HR 3.57) (log-rank test, p<0.001). In a subgroup analysis based on taxane-platinum vs. gemcitabine-platinum doublets, the rs238405 genotype was significantly related to OS in the taxane-platinum doublets group. However, the rs238416 genotype was significantly associated with OS in the gemcitabine-based group.
ERCC2 htSNPs rs50872 (overall), rs238405 (taxane-platinum doublets group), and rs238416 (gemcitabine-platinum doublets group) and infection related to first-line chemotherapy were associated with OS in unresectable NSCLC patients treated with first-line platinum-based chemotherapy. However, additional large prospective studies focusing on the role of ERCC2 htSNPs in unresectable NSCLC are needed.
Lung cancer (Amsterdam, Netherlands) 05/2012; 77(3):578-84. · 3.14 Impact Factor
ABSTRACT: PurposeWe investigated the efficacy and toxicity of a 4-week schedule of a fixed dose rate infusion of gemcitabine and weekly cisplatin
in elderly or poor performance status patients with unresectable non-small cell lung cancer (NSCLC).
MethodsIn this study, 48 patients with previously untreated NSCLC were given combination chemotherapy that consisted of gemcitabine
1,000mg/m2 (10mg/m2/min fixed dose rate infusion) and cisplatin 25mg/m2, and both drugs were given weekly on days1, 8 and 15.
ResultsA partial response and stable disease were observed in 20 patients (41.7%, 95% CI; 27.8–55.6%) and 12 patients (25.0%), respectively.
The overall median survival was 10.30months (range: 7.85–12.74months). Major toxicities included neutropenia (grade3 to
4, 29.2%) and infection (grade3 to 4, 27.1%).
ConclusionsOur results indicate that this regimen is a feasible treatment for elderly or poor performance status patients with unresectable
NSCLC. Nevertheless, the morbidity due to myelosuppression and infection following this treatment should be carefully considered.
Cancer Chemotherapy and Pharmacology 04/2012; 64(2):385-390. · 2.83 Impact Factor
ABSTRACT: Hypoxia-inducible factor-1α (HIF-1α), which plays an essential role in the adaptive response of cells to hypoxia, is associated with aggressive tumor behavior. Furthermore, a relationship between excision repair cross-complementing 1 (ERCC1) expression and platinum resistance has been reported in patients with various malignancies. The aim of this study was to investigate the expression of HIF-1α and ERCC1 and to elucidate the clinical significance of their expression in patients with small cell lung cancer (SCLC) treated with front-line platinum-based chemotherapy.
SCLC biopsy samples were obtained before front-line platinum-based chemotherapy from 111 patients with SCLC (limited disease, 29; extensive disease [ED], 82) between January 2002 and December 2009 at Gyeongsang National University Hospital. The expression levels of HIF-1α and ERCC1 were assessed by immunohistochemistry.
High expression levels of ERCC1 and HIF-1α were observed in 49 (44.1%) and 71 (64.0%) of 111 patients, respectively. Expression of ERCC1 and HIF-1α was not significantly associated with age, sex, Eastern Cooperative Oncology Group performance status, weight loss, or response to treatment, regardless of stage. In ED-SCLC, low expression in the HIF-1α group showed statistically better survival compared with high expression in the HIF-1α group (p = 0.018). Multivariate analysis revealed that response to front-line platinum-based chemotherapy (p < 0.001), good Eastern Cooperative Oncology Group performance status (0-1) (p = 0.002), and low expression of HIF-1α (p = 0.004) were independent predictors of better overall survival in ED-SCLC.
Low expression of HIF-1α may be a useful predictor of better overall survival in ED-SCLC patients treated with front-line platinum-based chemotherapy.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 03/2012; 7(3):528-34. · 4.55 Impact Factor
ABSTRACT: We investigated the efficacy and toxicity of a biweekly schedule of docetaxel and cisplatin in patients with metastatic non-small cell lung cancer (NSCLC).
In this study, 48 patients with previously untreated metastatic NSCLC were given combination chemotherapy consisting of docetaxel 40 mg/m(2) and cisplatin 40 mg/m(2); both drugs were given biweekly, on days 1 and 15, every 4 weeks.
A partial response and stable disease were observed in 25 patients (52.1%, 95% CI: 38.7-66.9%) and ten patients (20.8%), respectively. The overall median survival was 14.0 months (95% CI: 7.10-20.9 months). There was no treatment-related mortality. The major toxicity was grade 2 asthenia (35.4%). Grade 4 neutropenia was observed in two patients (4.2%), as was grade 3 infection (4.2%).
As a front-line chemotherapy in an outpatient setting for patients with metastatic NSCLC, the biweekly schedule of docetaxel and cisplatin showed effective antitumor activity with a marked reduction in hematologic toxicity, comparable to the results of previous studies using 3-week or weekly schedules. Further randomized studies are needed before this can be accepted as a standard schedule.
Lung cancer (Amsterdam, Netherlands) 09/2009; 69(1):94-8. · 3.14 Impact Factor
ABSTRACT: Combination chemotherapy with irinotecan and cisplatin is one of the standard treatments for patients with small-cell lung cancer (SCLC). In elderly patients, however, its efficacy and toxicity has not been well documented. In this Phase II study, we assessed the efficacy and toxicity of combination chemotherapy with irinotecan and cisplatin and examined whether advanced age compromises it in elderly patients with previously untreated extensive-disease small-cell lung cancer (ED-SCLC).
In this study, 46 previously untreated elderly patients (65 years or older) with ED-SCLC were given combination chemotherapy consisting of irinotecan 60 mg/m(2) on days 1, 8 and 15 and cisplatin 60 mg/m(2) on day 1. The treatment was repeated every 4 weeks until patients completed the maximum six cycles.
Patients consisted of 37 men and 9 women, whose median age was 70 years (range 65-81 years). A complete response and a partial response were observed in 19.6% (9/46) and 56.5% (26/46), respectively. The overall response rate was 76.1% (95% C.I; 63.8-88.4%). The overall median survival was 10.4 months (range 7.6-13.2 months). The median progression-free survival was 8.32 months (range 6.8-9.8 months). Major toxicities included neutropenia (grade 3-4, 58.7%), leukopenia (grade 3-4, 49.9%), infection (grade 3-4, 39.1%) and diarrhea (grade 3-4, 30.4%). Incidence of febrile neutropenia was significantly higher in patients with ECOG performance status 2-3 compared with ECOG performance status 0-1 (70.4% vs. 5.2%; p<0.001). There were two treatment related deaths in patients ECOG performance status 3.
Our results indicate that combination chemotherapy with irinotecan and cisplatin is an effective treatment for elderly patients with ED-SCLC who have good ECOG performance status and physicians should be aware of the mortality and morbidity due to myelosuppression following this treatment in elderly ED-SCLC patients with poor ECOG performance status.
Lung Cancer 02/2008; 61(2):220-6. · 3.43 Impact Factor
ABSTRACT: We conducted a phase II study of docetaxel and ifosfamide chemotherapy for patients with platinum-resistant or refractory non-small-cell lung cancer (NSCLC) to evaluate the response and toxicity profiles as a salvage treatment.
Between July 2000 and July 2004, 40 patients who had previously received platinum-based regimen as the first-line or second-line therapy were enrolled in this study. The treatment consisted of a docetaxel 75 mg/m(2) intravenous infusion on day 1 and intravenous ifosfamide 3 g/m(2) with Mesna uroprotectione on day 1 through 3. This regimen was repeated every 3 weeks.
One hundred thirty cycles of treatment were given, with a median of 3 cycles (range: 2 approximately 6 cycles). All the patients were evaluable for the response rate and toxicity profile. The major toxicity was myelosuppression. Grade 3 approximately 4 neutropenia occurred in 30 patients (75%) during treatment. Febrile neutropenia occurred in 16 patients (40%). Five of 40 patients (12.5%) had a partial response (95% confidence interval, 3.3 approximately 21.7%). The median time to disease progression was 2.65 months (range: 2.02 approximately 3.20 months), and the median survival was 5.24 months (range: 2.99 approximately 7.49 months).
Salvage chemotherapy with docetaxel and ifosfamide showed a low efficacy and a high proportion of severe neutropenia in patients with platinum-resistant or refractory advanced NSCLC.
Cancer Research and Treatment 10/2004; 36(5):287-92.