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: BackgroundWe performed a phase II study of combination chemotherapy with S-1 plus gemcitabine for treating chemo-naïve patients with
unresectable pancreatic cancer to evaluate the efficacy and toxicity.
Patients and methodsPatients with histologically confirmed unresectable pancreatic cancer were eligible. The treatment consisted of S-1 (40mg/m2 p.o. b.i.d. from D1 to 14) and gemcitabine (1,250mg/m2 on D1 and 8), repeated every 3weeks.
ResultsThirty-two patients were enrolled between March 2005 and December 2007. No complete response was observed and a partial response
was observed in 14 patients (44.0%), stable disease in eight patients (25.0%), and progressive disease in eight patients (25.0%).
The median time to progression was 4.92months (95% CI: 4.16–5.67months), and the median overall survival was 7.89months
(95% CI: 5.96–9.82months). The survival duration was significantly longer for the patients with a good performance status
compared with that of the patients with a poor performance status. The major toxicities were grade 3–4 neutropenia (9, 28.1%),
grade 3/4 thrombocytopenia (5, 15.6%), and grade 3 diarrhea (5, 15.6%).
ConclusionThe combination chemotherapy of S-1 and gemcitabine showed promising antitumor activity and manageable toxicities, and especially
for the good performance status patients with unresectable pancreatic cancer.
Cancer Chemotherapy and Pharmacology 04/2012; 64(4):707-713. · 2.83 Impact Factor
ABSTRACT: A phase II study was carried out to assess the efficacy and toxicity of combination chemotherapy with irinotecan, 5-fluorouracil (5-FU), and leucovorin (FOLFIRI) for the treatment of patients with metastatic or recurring gastric cancer previously treated with fluoropyrimidine-based chemotherapy.
Eligible patients were those who had metastatic gastric cancer previously treated with a fluoropyrimidine-based chemotherapy regimen or had disease recurrence within 6 months of completing adjuvant fluoropyrimidine-containing chemotherapy. Participants received irinotecan (150 mg/m² on day 1) and leucovorin (LV; 20 mg/m² on days 1-2) followed by continuous infusion of 5-FU (1500 mg/m² on days 1-2), every 2 weeks.
Between April 2006 and March 2008, 33 patients were enrolled in the study. FOLFIRI served as a second-line treatment in 27 patients, third-line treatment in 4 patients, and fourth-line treatment in 2 patients. The patients had a median age of 60 years (range, 40-75) and underwent 132 cycles of chemotherapy, with a median of 3 cycles (range, 1-15) per patient. The response rate was 18.2%, and the disease control rate was 36%. Median overall survival was 5.1 months (95% confidence interval, 3.74-6.45), and median time to progression was 2.3 months (95% confidence interval, 1.81-2.78). The major grade 3-4 toxicity was neutropenia (45.4%).
Combination chemotherapy with irinotecan, 5-FU, and LV is feasible in gastric cancer patients previously treated with fluoropyrimidine-based chemotherapy.
American journal of clinical oncology 12/2010; 33(6):572-6. · 2.21 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: We present an adult female patient who developed irreversible paraplegia and areflexia four days post intrathecal chemotherapy with methotrexate, cytosine arabinoside and hydrocortisone. On magnetic resonance imaging (MRI) of the lumbar spine, diffuse gadolinium enhancement of the anterior spinal nerve roots (ventral roots) was detected. Methylprednisolone was intravenously administered at a daily dose of 30mg/kg for three days. Despite this treatment, flaccid weakness in the lower extremities and urinary retention persisted. Following consolidation chemotherapy, no improvement in neurologic status was noted. Six months later, a follow-up MRI revealed severe atrophy of the thoracic spinal cord.
Yonsei Medical Journal 03/2008; 49(1):151-4. · 1.14 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.