Chee-Keong Toh

Never-Smokers With Lung Cancer: Epidemiologic Evidence of a Distinct Disease Entity

PURPOSE Tobacco smoke is a definite causative agent for lung cancer. It is increasingly being recognized that never-smokers can be afflicted with non-small-cell lung cancer (NSCLC). We aim to assess survival differences between smokers and never-smokers with NSCLC. PATIENTS AND METHODS We analyzed 975 NSCLC patients who presented from January 1999 to December 2002. Clinical characteristics among current-, former- and never-smokers were tested using chi2 or Kruskal-Wallis test. The hazard ratio (HR) for death and its 95% CI were calculated by Cox regression. RESULTS Of 975 patients, 59 had no smoking history and 33 had no quit time recorded. Of 883 patients analyzed, 286 patients (32.4%) were never-smokers. One hundred ninety-six never-smokers (68.5%) were females compared with 12% among current- and 13% among former-smokers (P < .001). There was a significant difference in histologic subtype between never-smokers and smokers: 69.9% with adenocarcinoma versus 39.9% (current-smokers) versus 47.3% (former-smokers); 5.9% with squamous cell carcinoma versus 35.7% (current-smokers) versus 28% (former-smokers; P < .001). Smokers had significantly poorer performance status (P = .002) and higher median age at diagnosis (P < .001) while more never-smokers presented with advanced disease (P = .002). Eight hundred and five patients (82.6%) died by May 30, 2005. The HR for smokers was significantly higher on both univariate and multivariate analysis (HR, 1.297; 95% CI, 1.040 to 1.619). CONCLUSION Never-smokers comprised a high proportion of NSCLC patients in Singapore. Definite epidemiologic differences exist between never-smokers and smokers. Differences in survival outcome further suggest that the biology underlying the pathogenesis and behavior of the disease may be different for never-smokers.

Phase I pharmacokinetic study of a weekly liposomal paclitaxel formulation (Genexol®-PM) in patients with solid tumors

BACKGROUND The aim of this study was to determine the maximum tolerated dose (MTD) and the pharmacokinetic profile of Genexol-PM in Asian cancer patients. MATERIALS AND METHODS Patients (N = 24) refractory to previous chemotherapy received Genexol-PM as an 1-h infusion on a weekly basis for 3 weeks followed by a resting week. The starting dose was 80 mg/m(2) and the maximum administered dose was 200 mg/m(2). RESULTS The majority of patients had lung, nasopharyngeal and breast cancers and in eleven patients (46%), taxane-based chemotherapy had previously failed. The MTD was defined at 180 mg/m(2). The most common grade 3 non-hematologic adverse events in cycle 1 were fatigue (4%) and neuropathy (4%) occurring mainly at 200 mg/m(2). Five (21%) patients had partial response, nine (38%) had stable disease and seven (29%) had disease progression. Five of 11 previously taxane-refractory patients showed clinical benefit to Genexol-PM. The pharmacokinetics of Genexol-PM displayed dose-proportionality, with both the maximum concentration (C(max)) and the area under the concentration-time curve from zero to infinity (AUC(0-infinity)) increasing by approximately four- and threefold, respectively, as the dose of Genexol-PM was escalated from 80 to 200 mg/m(2). The median total-body clearance of Genexol-PM for all patients was 43.9 l/h. CONCLUSION The weekly regimen of Genexol-PM was well tolerated and responses were observed in patients with refractory tumors, including patients who had failed taxane-based chemotherapy previously.

Lung cancer in never-smokers

The mystery behind never-smokers being more prone to lung cancer is unlocked with regard to smoking status and sex Never-smokers with lung cancer constitute an understudied and under-represented subset of patients. Although there have been hints that never-smokers can be afflicted with lung cancer,1 especially among Asian Chinese women,2 it is only recently that attention has turned towards this much ignored group of patients. Sparking the attention was the finding that somatic mutations of the epidermal growth factor receptor (EGFR) were consistently more common among lung tumours of never-smokers,3 and that these mutations could possibly explain the higher response rates to single agent gefitinib.4,5 The attention was further intensified by media reports of a non-smoking wife of a celebrity who developed lung cancer. Most studies on never-smokers with lung cancer have emerged from Asia, as the smoking prevalence rates in Asia are lower compared with the West. In Singapore, where the population is predominantly Chinese, the smoking prevalence in the general population is 24.3% in men and 3.6% in women.6 About 10–15% of lung cancers occur in a lifetime among never-smokers in the West,7 whereas about 30–40% of patients with lung cancer are never-smokers among the Asian countries.8 Whether this represents a higher risk of lung cancer among never-smokers in Asia or is a mere reflection of the higher numbers of never-smokers at risk is unclear at present. A recent large prospective study by Thun et al 9 may help to put things in perspective. The study among African Americans and Whites provides estimates of mortality due to lung cancer among never-smokers, with rates of 17.1 and 14.7 per 100 000 person-years among men and women, respectively. These figures highlight that the burden of lung cancer among never-smokers is fairly significant among …

A Phase II Study of Pazopanib in Asian Patients with Recurrent/Metastatic Nasopharyngeal Carcinoma

Purpose: Nasopharyngeal carcinoma is endemic in Asia and angiogenesis is important for growth and progression. We hypothesized that pazopanib would have antiangiogenic activity in nasopharyngeal carcinoma. Experimental Design: A single arm monotherapy study of pazopanib in patients with WHO type II/III nasopharyngeal carcinoma who had metastatic/recurrent disease and failed at least one line of chemotherapy. A Simons optimal 2-stage design was used. Patients with Eastern Cooperative Oncology Group (ECOG) 0-2 and adequate organ function were treated with pazopanib 800 mg daily on a 21-day cycle. The primary endpoint was clinical benefit rate (CR/PR/SD) achieved after 12 weeks of treatment. Secondary endpoints included toxicity and progression-free survival. Exploratory studies of dynamic-contrast enhanced computed tomography (DCE-CT) paired with pharmacokinetics (PK) of pazopanib was done. Results: Thirty-three patients were accrued. Patients were ECOG 0-1 with median age of 50 years (range 36–68). There were 2 (6.1%) partial responses, 16 (48.5%) stable disease, 11 (33.3%) progressive disease, 4 (12.1%) were not evaluable for response. The clinical benefit rate was 54.5% (95% CI: 38.0–70.2). Ten patients (30.3%) received more than 6 cycles (4 months) of treatment and 7 (21.2%) had PR/SD that lasted at least 6 months. One patient each died from epistaxis and myocardial infarction. Common grade 3/4 toxicities included fatigue (15.2%), hand-foot syndrome (15.2%), anorexia (9.1%), diarrhea (6.1%), and vomiting (6.1%). Serial DCE-CT scans show significant reductions in tumor blood flow, permeability surface area product, and fractional intravascular blood volume. Conclusion: Pazopanib showed encouraging activity in heavily pretreated nasopharyngeal carcinoma with an acceptable toxicity profile. Clin Cancer Res; 17(16); 5481–9. ©2011 AACR.

Docetaxel is effective in heavily pretreated patients with disseminated nasopharyngeal carcinoma

BACKGROUND To evaluate the efficacy and toxicity of single-agent docetaxel (Taxotere) as therapy in patients with disseminated nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS Patients with histologically confirmed metastatic or recurrent NPC who have failed at least one line of palliative chemotherapy regimen but no prior docetaxel were eligible. Patients received weekly docetaxel every 28 days (docetaxel 30 mg/m(2) on days 1, 8 and 15) and were evaluated every two cycles of treatment of response assessment. Quality-of-life (QoL) assessments during the treatment period were done using the European Organization for Research and Treatment of Cancer QoL questionnaire QLQ-C30; version 3.0. RESULTS Thirty patients were assessable for toxicity and response. The median age of the patients was 47 years (range 25-68 years) and the majority of patients had good performance status (Eastern Cooperative Oncology Group 0-1). Grade 3 or 4 toxicity included fatigue (13%), anemia (10%) and diarrhea (3%) of patients. Eleven (37%) and four (13.3%) patients achieved partial response and stable disease, respectively. The median progression-free survival was 5.3 months and median overall survival of 12.8 months. The partial responders had a mean duration of response of 4.1 months. Docetaxel caused a significant decline in QoL scores during treatment of patients responding or progressing with the treatment. CONCLUSIONS Our findings suggest that weekly docetaxel is well tolerated and is an active agent in patients with disseminated NPC who were previously exposed and largely refractory to platinum-based chemotherapy but can cause a significant decline in QoL during treatment.

Correlation between epidermal growth factor receptor mutations and expression of female hormone receptors in East-Asian lung adenocarcinomas.

Introduction: Epidermal growth factor receptor (EGFR) mutations are more common in lung adenocarcinoma and in female patients of East-Asian origin. We aimed to assess the expression of female hormone receptors in East-Asian lung adenocarcinomas, their correlation with EGFR mutations, and prognostic significance. Methods: Estrogen receptor (ER)&agr;, ER&bgr;, progesterone receptor (PR), and Her-2 expression were examined using immunohistochemical methods on 109 lung adenocarcinoma cases. EGFR mutations were analyzed by partially denaturing high performance liquid chromatography. Association of hormone receptor with clinical factors was assessed using the Fishers exact test. Associations with survival were assessed using the Cox proportional hazard model. Results: Using scoring criteria routinely used for breast cancer, there were four (4%) ER&agr;, one (1%) ER&bgr;, six (6%) PR, and one (1%) Her-2 positive cases. Considering any staining as positive, 14 (14%) ER&agr;, 10 (9%) ER&bgr;, 12 (12%) PR, and 26 (24%) Her-2 cases were positive. Thirty-nine patients (39%) had EGFR mutations. ER&agr; positivity was significantly associated with ER&bgr; and PR positivity. There were more EGFR mutations seen in tumors with ERß positivity (60%) compared with those with negative expression (37.9%), and there was a trend toward a poorer outcome for patients with tumor that were positive for ERß and Her-2. Conclusions: We found that ER&agr;, ER&bgr;, PR, and Her-2 expression in lung adenocarcinoma are present but limited. This suggests that hormonal influence may not be an important factor to account for the high prevalence of lung cancer among the East-Asian women.

Phase II study of irinotecan (CPT-11) as salvage therapy for advanced nasopharyngeal carcinoma (NPC)

5576 Background: Advanced NPC is chemosensitive and responsive even to third-line salvage regimen, therefore the continued search for active agents to enhance salvage potential. Topoisomerase I targeters have been shown to induce apoptosis in NPC cell lines in in-vitro experiments. This phase II study was designed to evaluate efficacy and safety of irinotecan in patients with advanced NPC. The pharmacokinetic and pharmacogenetic study component is reported separately. METHODS Eligibility criteria included AJCC stage IVC nasopharyngeal undifferentiated carcinoma, ECOG performance status (PS) 0-2, progressive disease during or less than 3 months after platinum-based and/or taxane-based regimen, and bidimensionally measurable disease. Irinotecan at 100 mg/m2 was administered on days 1, 8, 15, every 28 days up to maximum of 6 cycles, or until disease progression or appearance of non-tolerable toxicity. Tumor response was evaluated after every 2 cycles based on WHO criteria. RESULTS Between September 2001 and November 2003, 30 patients were enrolled. Currently data is available for 25 patients. Patient characteristics included mean age 50.9 (standard deviation - SD 7.5), 21 males; 4 females, 23 (92%) are Chinese, 22 (88%) had ECOG PS 0-1, and a mean 2.0 (SD 1.8) prior lines of chemotherapy. To date, all 25 patients are evaluable for toxicity with a mean 3.0 (SD 1.6) cycles of irinotecan administered. Severe toxicities of greater than grade 3 (WHO) included: grade 3 neutropenia -3 (12%), grade 3 anemia -5 (20%), grade 3 and 4 diarrhea -2 (8%) and 1 (4%) respectively, grade 3 alkaline phosphatase elevation -2 (8%). With a median follow up of 183 days (range 8 -476 days), outcome data is currently available for 23 patients. Best responses included 4 (17%) partial responses, 1 (4%) stable disease and 18 (78%) progressive disease. By Kaplan-Meier method, median progression free survival was 111 days and median overall survival was 303 days. CONCLUSIONS Preliminary results from this trial suggest that irinotecan is an active agent as salvage treatment with modest toxicity in patients with advanced NPC refractory to platinum/taxane-based chemotherapy. No significant financial relationships to disclose.

An inflammatory response with worsening of pleural effusion on treatment with erlotinib in non-small cell lung cancer

Department of Medical Oncology, National Cancer Centre, Singapore, Department of Respiratory & Critical Care Medicine, Singapore General Hospital, Singapore, Laboratory of Clinical Pharmacology, National Cancer Centre, Singapore, Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Laboratory Medicine Service, Changi General Hospital, Singapore and Department of Pathology, Singapore General Hospital, Singapore

Metronomic chemotherapy: A relook at its basis and rationale

Metronomic administration of chemotherapy has long been recognized as having a different biological effect from maximal tolerated dose (MTD) administration. Preclinical studies have demonstrated these differences quite elegantly and many clinical trials have also demonstrated reproducible activity albeit small, in varied solid malignancies even in patients who were heavily pretreated. However, the concept of metronomic chemotherapy has been plagued by lack of a clear definition resulting in the published literature that is rather varied and confusing. There is a need for a definition that is mechanism(s)-based allowing metronomics to be distinguished from standard MTD concept. With significant advances made in understanding cancer biology and biotechnology, it is now possible to attain that goal. What is needed is both a concerted effort and adequate funding to work towards it. This is the only way for the oncology community to determine how metronomic chemotherapy fits in the overall cancer management schema.

Gefitinib in Combination with Gemcitabine and Carboplatin in Never Smokers with Non-small Cell Lung Carcinoma: A Retrospective Analysis

Introduction: Randomized placebo-controlled phase III trials failed to show a survival benefit with the addition of gefitinib to platinum-based combination chemotherapy as first-line therapy in unselected patients with advanced non-small cell lung cancer (NSCLC). We conducted a retrospective analysis of the outcome in never smokers with advanced NSCLC who received gemcitabine-carboplatin-gefitinib (GCI) as first-line therapy and compared these patients with a historical control group who received gemcitabine-carboplatin (GC) alone in our center. Methods: Never-smoker patients with chemonaive stage IIIB or IV NSCLC were treated with GCI. These patients were compared with a historical control group of never smokers who had been treated with GC alone as the first-line therapy. Results: A total of 80 patients were reviewed: 51 patients were treated with GCI and 29 with GC. Most patients were women, and adenocarcinoma was the most common histologic subtype. The response rate for patients in the GCI group was 62.7% (95% confidence interval [CI] = 48.08–75.87), which was higher than that of the GC group, 27.6% (95% CI = 12.73–47.24). The GCI group showed a significant improvement in progression-free survival compared with the GC group (hazard ratio of 0.19, 95% CI = 0.105–0.351, p < 0.001). The median overall survival for the patients on GCI was 20.5 months compared 14.1 months (p = 0.05) for patients on GC. Conclusion: The addition of gefitinib to first-line chemotherapy improved progression-free survival and overall survival when used as a first-line therapy in never smokers with advanced NSCLC in this retrospective study. A prospective randomized phase III study is needed to confirm this finding.