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2.  A double-blind randomized discontinuation phase II study of sorafenib (BAY 43-9006) in previously treated non-small cell lung cancer patients: Eastern Cooperative Oncology Group study E2501 
Introduction
Sorafenib is a raf kinase and angiogenesis inhibitor with activity in multiple cancers. This phase II study in heavily pretreated non-small cell lung cancer (NSCLC) patients (≥ two prior therapies) utilized a randomized discontinuation design.
Methods
Patients received 400 mg of sorafenib orally twice daily for two cycles (two months) (Step 1). Responding patients on Step 1 continued on sorafenib; progressing patients went off study, and patients with stable disease were randomized to placebo or sorafenib (Step 2), with crossover from placebo allowed upon progression. The primary endpoint of this study was the proportion of patients having stable or responding disease two months after randomization.
Results
: There were 299 patients evaluated for Step 1 with 81 eligible patients randomized on Step 2 who received sorafenib (n=50) or placebo (n=31). The two-month disease control rates following randomization were 54% and 23% for patients initially receiving sorafenib and placebo respectively, p=0.005. The hazard ratio for progression on Step 2 was 0.51 (95% CI 0.30, 0.87, p=0.014) favoring sorafenib. A trend in favor of overall survival with sorafenib was also observed (13.7 versus 9.0 months from time of randomization), HR 0.67 (95% CI 0.40-1.11), p=0.117. A dispensing error occurred which resulted in unblinding of some patients, but not before completion of the 8 week initial step 2 therapy. Toxicities were manageable and as expected.
Conclusions
: The results of this randomized discontinuation trial suggest that sorafenib has single agent activity in a heavily pretreated, enriched patient population with advanced NSCLC. These results support further investigation with sorafenib as a single agent in larger, randomized studies in NSCLC.
doi:10.1097/JTO.0b013e31826149ba
PMCID: PMC3444827  PMID: 22982658
NSCLC; sorafenib; randomized discontinuation trial
4.  Survival following non-small cell lung cancer among Asian/Pacific Islander, Latina, and non-Hispanic White women who have never smoked 
BACKGROUND
Lung cancer is the leading cause of cancer death among US Asian/Pacific Islander (API) and Latina women, despite low smoking prevalence. This study examined survival patterns following non-small cell lung cancer in a population-based sample of lung cancer cases from the San Francisco Bay Area Lung Cancer Study (SFBALCS).
METHODS
Women diagnosed with lung cancer from 1998–2003 and 2005–2008 and identified through the Greater Bay Area Cancer Registry were telephone-screened for eligibility for the SFBALCS. The screener data were linked to the cancer registry data to determine follow-up. This analysis included 187 non-Hispanic White, 23 US-born Latina, 32 foreign-born Latina, 30 US-born API, and 190 foreign-born API never smokers diagnosed with lung cancer and followed through 2008.
RESULTS
All-cause survival was poorer among APIs (hazard ratio (HR) and 95% confidence interval (CI) = 1.7 (1.0–2.8) among US-born APIs; 1.2 (0.9–1.5) among foreign-born APIs), and Latinas (HR (95% CI) = 2.1 (1.2–3.6) among US-born Latinas; 1.4 (0.9–2.3) among foreign-born Latinas), relative to non-Hispanic Whites. These survival differences were not explained by differences in selected sociodemographic or clinical factors.
CONCLUSIONS
Further research should focus on factors such as cultural behaviors, access to or attitudes toward health care, and genetic variations, as possible explanations for these striking racial/ethnic differences.
IMPACT
Latina and API female never smokers diagnosed with lung cancer were up to two-times more likely to die than non-Hispanic Whites, highlighting the need for additional research to identify the underlying reasons for the disparities, as well as heightened clinical awareness.
doi:10.1158/1055-9965.EPI-10-0965
PMCID: PMC3070404  PMID: 21239685
lung cancer survival; Asian; Latina; Hispanic; never smokers; nativity
5.  A phase I dose-escalation and pharmacokinetic study of enzastaurin and erlotinib in patients with advanced solid tumors 
Cancer Chemotherapy and Pharmacology  2011;69(4):1013-1020.
Purpose
Enzastaurin, an oral serine/threonine kinase inhibitor, targets the protein kinase C and AKT pathways with anti-tumor and anti-angiogenic effects. Erlotinib, an oral epidermal growth factor receptor (EGFR) inhibitor, has activity in solid tumors. Based on the promising combination of EGFR inhibitors and anti-angiogenic agents, this phase I trial was initiated.
Methods
This single-institution, open-label, non-randomized trial used a standard 3 + 3 dose-escalation model in patients with advanced solid malignancies including non-small-cell lung cancer (NSCLC). Two dose levels of enzastaurin (with loading doses) were explored: 250 mg daily and 500 mg daily. Erlotinib was given at 150 mg daily.
Results
Sixteen patients were enrolled in this study (median age, 64 years). Most patients were heavily pre-treated, female, and Caucasian and had NSCLC. The highest dose of enzastaurin, 500 mg daily, was tolerated with no unexpected adverse events and no alteration in the pharmacokinetics of either drug at this dose level. The mean clearance was 5.75 L/h for erlotinib and 53.8 L/h for enzastaurin. The most common possibly drug-related grade 3–4 adverse events included diarrhea (25.0%), neurologic symptoms (18.8%), and vomiting (18.8%). Activity was noted, with a partial response in one patient and prolonged disease stability for >12 cycles in three patients.
Conclusion
The combination of enzastaurin 500 mg daily and erlotinib 150 mg daily is well tolerated and does not alter the pharmacokinetics of the individual drugs, with clinical activity seen. A phase II trial of this combination has been initiated in patients with advanced-stage NSCLC.
doi:10.1007/s00280-011-1792-8
PMCID: PMC3313020  PMID: 22160298
Clinical trial; Enzastaurin; Erlotinib; Pharmacokinetics
6.  Adjuvant Chemotherapy for Early Stage Non-Small Cell Lung Cancer 
For many years adjuvant chemotherapy has been a standard treatment after complete resection in malignancies such as breast and colon but only recently has its use become standard in early stage non-small cell lung cancer (NSCLC). Although surgery is regarded as the best possible treatment for early stage NSCLC, only 20–25% of patients have resectable disease at presentation. Despite optimal surgical treatment, 5-year survival rates for NSCLC remain 50–60% for stage IB, 40–50% for stage II, and 20–30% for stage III (Kohler et al., 2011; Siegel et al., 2011). Adjuvant chemotherapy provides additional survival benefit in resected NSCLC but questions remain as to how to select patients for therapy and which regimen is best. Other than work with tegafur/uracil in Japan, the positive adjuvant trials have all utilized a cisplatin backbone, but the drug(s) to pair with cisplatin are a matter of debate and will be discussed further in this manuscript.
doi:10.3389/fonc.2011.00045
PMCID: PMC3356017  PMID: 22655247
lung cancer; non-small cell; adjuvant; chemotherapy; early stage
7.  Lung cancer incidence in never-smokers 
Purpose
Lung cancer is a leading cause of cancer death worldwide. While smoking remains the predominant cause of lung cancer, lung cancer in never-smokers is an increasingly prominent public health issue. Data on this topic, particularly lung cancer incidence rates in never-smokers, however, are limited.
Methods
We review the existing literature on lung cancer incidence and mortality rates among never-smokers and present new data regarding rates in never-smokers from large, population-based cohorts: 1) Nurses’ Health Study, 2) Health Professionals Follow-up Study, 3) California Teachers Study, 4) Multiethnic Cohort Study, 5) Swedish Lung Cancer Register in the Uppsala/Örebro region, and the 6) First National Health and Nutrition Examination Survey Epidemiologic Follow-up Study.
Results
Truncated age-adjusted incidence rates of lung cancer among never-smokers aged 40 to 79 years in these six cohorts ranged from 14.4 to 20.8 per 100,000 person-years in women and 4.8 to 13.7 per 100,000 person-years in men, supporting earlier observations that women are more likely than men to have non-smoking-associated lung cancer. The distinct biology of lung cancer in never-smokers is apparent in differential responses to epidermal growth factor receptor inhibitors and an increased prevalence of adenocarcinoma histology in never-smokers.
Conclusion
Lung cancer in never-smokers is an important public health issue needing further exploration of its incidence patterns, etiology, and biology.
doi:10.1200/JCO.2006.07.2983
PMCID: PMC2764546  PMID: 17290054
8.  Review of erlotinib in the treatment of advanced non-small cell lung cancer 
Biologics : Targets & Therapy  2007;1(4):335-346.
Epidermal growth factor receptor (EGFR) is a transmembrane receptor with a cytoplasmic tyrosine kinase (TK) domain present on many solid tumors including non-small cell lung cancer (NSCLC). Once stimulated by ligand, the downstream pathway is activated leading to cell growth, survival, and carcinogenesis. There are several methods of EGFR inhibition including monoclonal antibodies directed against the external region and small molecule inhibitors of TK domain. Erlotinib and gefitinib are orally available small molecule EGFR TK inhibitors, with proven efficacy in NSCLC. The most common side effects are skin toxicity and diarrhea. Erlotinib has been shown to improve survival compared to placebo in second or third-line therapy for NSCLC. However, erlotinib in combination with chemotherapy failed to show a survival advantage in two first-line studies which could be due to the timing of chemotherapy administration. In general, patients with adenocarcinoma histology, female gender, Asian ethnicity, and never smokers have a better response when treated with erlotinib. This could be related to the presence of EGFR mutations, lack of KRAS mutations, or overexpression of EGFR as measured by fluorescent in-situ hybridization (FISH) analysis. Future studies should concentrate on further development of predictors of clinical benefit with erlotinib, overcoming resistance to erlotinib that develops in initial responders, as well as more effective sequencing of erlotinib with chemotherapy and combinations of the drug with other “targeted” therapeutic agents.
PMCID: PMC2721286  PMID: 19707304
epidermal growth factor receptor; erlotinib; non-small cell lung cancer

Results 1-8 (8)