Swan-Swan Leong

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.

A phase II study evaluating the safety and efficacy of an adenovirus-ΔLMP1-LMP2 transduced dendritic cell vaccine in patients with advanced metastatic nasopharyngeal carcinoma

BACKGROUND Individuals with metastatic Epstein-Barr virus (EBV)-positive nasopharyngeal carcinoma (NPC) continue to have poor outcomes. To evaluate the ability of a dendritic cell (DC) vaccine to target subdominant EBV antigens LMP1 and LMP2 expressed by NPC cells, we vaccinated patients using autologous DCs transduced with an adenovirus encoding a truncated LMP1 (ΔLMP1) and full-length LMP2 (Ad-ΔLMP1-LMP2). MATERIALS AND METHODS Sixteen subjects with metastatic NPC received Ad-ΔLMP1-LMP2 DC vaccines i.d. biweekly for up to five doses. Toxicity, immune responses and clinical responses were determined. RESULTS Most patients had extensive disease, with a median of three visceral sites of involvement (range 1-7). No significant toxicity was observed. Ad-ΔLMP1-LMP2 DCs induced delayed type hypersensitivity responses in 9 out of 12 patients, but although these DCs activated LMP1/2-specific T cells in vitro, no such increase in the frequency of peripheral LMP1/2-specific T cells was detected. Three patients had clinical responses including one with partial response (for 7½ months) and two with stable disease (for 6½ and 7½ months). CONCLUSIONS Ad-ΔLMP1-LMP2 transduced DCs can be successfully generated and safely administered to patients with advanced NPC. Since efficacy was limited, future studies should focus on DC vaccines with greater potency administered to subjects with less tumor burden.

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 III randomized trial of radiotherapy versus concurrent chemo-radiotherapy followed by adjuvant chemotherapy in patients with AJCC/UICC (1997) stage 3 and 4 nasopharyngeal cancer of the endemic variety

5500 Background: Intergroup 00-99 study for Nasopharyngeal Cancer (NPC) showed a benefit of adding chemotherapy to radiotherapy (RT). This study aimed to confirm the findings of 00-99 in patients from an endemic region. Specific objectives were to compare the rates of distant metastases, disease free (DFS) and overall survival (OS). METHODS 221 patients were randomized between 9/1997 to 5/2003. 220 are included in this analysis. 109 received radiotherapy (R) alone and 111 had chemo-radiotherapy (C). Patients were all staged by CT / MR, CXR, liver and bone imaging. All had AJCC(1997) Stage 3 or 4 disease as well as WHO Type II or III histology. All patients (C & R) received 70Gy in 7 wks using standard RT portals and techniques. Those on (C) received concurrently cisplatin (25mg/m2 D1-4) on wks 1,4 and 7 of RT and adjuvant cisplatin (20mg/m2 D1-4) and 5FU (1000mg/m2 D1-4) every 4 wks (wk 11, 15, 19) for 3 cycles following completion of RT. RESULTS All patients were followed up for a minimum of 6 mths. 45% had Stage III and 54% Stage IV disease. 2 patients were non-compliant in the R arm. In the C arm, 40% had dose reduction / reduced cycles of chemo during the concurrent phase; 31% did not receive any adjuvant chemotherapy; and another 27% had dose reduction / reduced or delayed cycles of chemo. 6 patients had their RT dose reduced. To date, 59 patients (37 R, 22 C) have died. Cause of death was disease-related for 51 (32 R, 19 C) . Median survival time for R was 49.9 months, but this has not been reached for those on C. 2-year DFS rates were 62% for R and 76% for C. Hazard ratio (HR) was 0.67 (95% CI: 0.42 to 1.08, p = 0.10). 2-year cumulative incidence rate for distant metastasis was 28% (95% CI 18% to 37%) for R and 14% (95% CI 7% to 21%) for C. (p = 0.034). 2-year OS rates were 77% for R and 85% for C respectively. The HR estimate was 0.54 (95% CI: 0.32 to 0.89, p = 0.02). CONCLUSIONS This trial confirms the results of Intergroup 0099 and the results are shown to be applicable to the endemic type of NPC. This study also confirms that chemotherapy improves distant control in NPC. No significant financial relationships to disclose.

Chemotherapy with or without radiotherapy in patients with locoregionally recurrent nasopharyngeal carcinoma

Treatment of locoregionally recurrent nasopharyngeal carcinoma (NPC) is challenging because of prior radiotherapy, morbidities from disease recurrence, and limited therapeutic options available.

Graft-vs-tumor effect in patients with advanced nasopharyngeal cancer treated with nonmyeloablative allogeneic PBSC transplantation

While nonmyeloablative peripheral blood stem cell transplantation (NST) has shown efficacy against several solid tumors, it is untested in nasopharyngeal cancer (NPC). In a phase II clinical trial, 21 patients with pretreated metastatic NPC underwent NST with sibling PBSC allografts, using CY conditioning, thymic irradiation and in vivo T-cell depletion with thymoglobulin. Stable lymphohematopoietic chimerism was achieved in most patients and prophylactic CYA was tapered at a median of day +30. Seven patients (33%) showed partial response and three (14%) achieved stable disease. Four patients were alive at 2 years and three showed prolonged disease control of 344, 525 and 550 days. With a median follow-up of 209 (4–1147) days, the median PFS was 100 days (95% confidence interval (CI), 66–128 days), and median OS was 209 days (95% CI, 128–236 days). Patients with chronic GVHD had better survival—median OS 426 days (95% CI, 194–NE days) vs 143 days (95% CI, 114–226 days) (P=0.010). Thus, NST may induce meaningful clinical responses in patients with advanced NPC.

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.