Ruqin Chen

A retrospective analysis of outcomes by age in a three-arm phase III trial of gemcitabine in combination with carboplatin or paclitaxel vs. paclitaxel plus carboplatin for advanced non-small cell lung cancer

PURPOSE Sufficient data are currently unavailable to assist in defining suitable regimens for patients ≥ 70 years with advanced non-small cell lung cancer (NSCLC). METHODS Chemonaïve patients with a performance status (PS) of 0 or 1 and stage IIIB or IV NSCLC were randomized to gemcitabine 1000mg/m(2) on days 1 and 8 plus carboplatin area under the curve (AUC) 5.5 on day 1; the same schedule of gemcitabine plus paclitaxel 200mg/m(2) on day 1; or paclitaxel 225mg/m(2) on day 1 plus carboplatin AUC 6.0 on day 1. Cycles were every 21 days up to 6. Efficacy and toxicity results were compared by age groups. RESULTS Overall survival (OS) between patients <70 years (8.6 months, 95% CI: 7.9, 9.5) and ≥ 70 years (7.9 months, 95% CI: 7.1, 9.5) was similar. OS was 8.8 months (95% CI: 7.5, 10.3) among patients 70-74 years, 6.5 months (95% CI: 5.6, 9.3) among patients 75-79 years, and 7.9 months (95% CI: 6.3, 10.3) among patients ≥ 80 years. OS was lower among patients 75-79 years compared with patients 70-74 years (P=0.04). Compared with patients <70 years, patients ≥ 70 years experienced similar rates of myelosuppresion, but younger patients experienced more vomiting and nausea. There was no clear pattern with respect to differences in efficacy by treatments across age groups. CONCLUSIONS Based on the similarity of patient outcomes across age groups, doublet chemotherapy is feasible among carefully selected elderly patients with good PS.

Pemetrexed in Relapsed Small-Cell Lung Cancer and the Impact of Shortened Vitamin Supplementation Lead-In Time: Results of a Phase II Trial

Introduction: We undertook a phase II trial to assess the efficacy and safety of single-agent pemetrexed (P) in relapsed small-cell lung cancer (SCLC) patients. Methods: Patients had limited- or extensive-stage SCLC, performance status 0 to 2, and one prior chemotherapy regimen. Initial P dose was 500 mg/m2 every 21 days. Planned sample sizes were 36 sensitive (S) patients in a two-stage sequential fashion with early stopping rule, and 25 refractory (R) patients in a single-stage design without stopping rule. Patients received folic acid and Vitamin B12 prior to P, and B12 could be given up until P treatment. Primary outcome measure was response rate. Results: Enrollment occurred from July 2004 to March 2006. The stopping rule was invoked when <3 of 14 S patients responded. The protocol was amended to evaluate P 900 mg/m2 in cohorts of 40 S and 40 R patients. Overall, 121 patients were enrolled, with 116 patients treated. S (n = 53) and R (n = 63) patients were analyzed separately at both dose levels. Across the 4 treatment groups (S500, S900, R500, R900), 1 patient (2.63%) in the S900 group had a partial response. Overall, 18 patients (16%) had stable disease. Eighty-seven patients (75%) had progressive disease. Responses were not evaluable in 10 patients (8.6%). Overall response rate was 0.9%. Across treatment groups, disease control rates (partial response + stable disease) were 20%, 15.8%, 21.7%, and 12.5%, respectively. Median time to progression ranged from 1.2 to 1.5 months, median survival times ranged from 2.5 to 6.1 months, and 1-year survival rates ranged from 5.6 to 25.8%. Common grade 3/4 hematologic toxicities (at 500 and 900 mg/m2) were neutropenia (16%; 9%) and leukopenia (11%; 8%), and nonhematologic toxicities were dyspnea (11%; 10%) and fatigue (16%; 9%). Retrospective analysis of cycle 1 events by timing of B12 administration showed no trend toward more frequent serious toxicities when B12 was given <7 days prior to P. Conclusions: Single-agent P 500 mg/m2 shows minimal activity in relapsed SCLC patients. P can be given at 900 mg/m2 without significant increase in serious toxicities, but does not seem to increase efficacy. B12 given <7 days before P does not seem to be associated with increased serious toxicities.

Outcomes Associated with Brain Metastases in a Three-Arm Phase III Trial of Gemcitabine-Containing Regimens Versus Paclitaxel Plus Carboplatin for Advanced Non-small Cell Lung Cancer

Background: Brain metastases (BMs) are a common complication of non-small cell lung cancer (NSCLC). Because of historical data indicating a poor prognosis for patients with BM, few randomized phase III studies of advanced NSCLC have included patients with BM at presentation. Because the potential benefits of systemic therapy in patients with BM are uncertain, we analyzed data from a recent phase III study. Methods: One thousand one hundred thirty-five chemonaïve patients with stage IIIB/IV NSCLC were randomized to receive gemcitabine/carboplatin, gemcitabine/paclitaxel, or paclitaxel/carboplatin. Stratification was based on presence or absence of BM, stage, and baseline weight loss. Patients with BM were required to be clinically stable after treatment with radiotherapy or surgery before entry. Results were retrospectively analyzed by presence or absence of BM at study entry. Results: Rate of BM was 17.1% overall. The response rate was 28.9% for patients with BM (n = 194) versus 29.1% without BM (n = 941). Time to progression was 4.3 months with BM and 4.6 months without BM (p = 0.03). Median survival was 7.7 months (95% confidence interval: 6.7–9.3) among patients with BM (n = 194) and 8.6 months (95% confidence interval: 7.9–9.5) for patients without BM (n = 941), p = 0.09. Rates of hematologic adverse events were not different among patients with and without BM. Conclusions: There were no significant differences in response, survival, or hematologic toxicity for patients with or without BM; however, patients with BM had a small but significantly shorter time to progression. Nonprogressing patients with treated BM are appropriate candidates for systemic therapy and entry into clinical trials.

Phase 1/2 dose escalating study of twice-monthly pemetrexed and gemcitabine in patients with advanced cancer and non-small cell lung cancer.

Introduction: Pemetrexed is synergistic with gemcitabine in preclinical models of non-small cell lung cancer (NSCLC). The optimal dose and utility of gemcitabine and pemetrexed was evaluated in a dose-escalating study. Methods: The phase 1 study included patients with advanced tumors, whereas the phase 2 study included patients with locally advanced or metastatic NSCLC. Gemcitabine was infused over 30 minutes, followed by pemetrexed administered over 10 minutes on day 1 of a 14-day cycle. Treatment continued for 12 cycles or until disease progression. All patients received folic acid, Vitamin B12, and steroid prophylaxis. Results: Maximum tolerated dose was gemcitabine 1500 mg/m2, followed by pemetrexed 500 mg/m2. Fifty-three patients (29 male, 24 female) were enrolled in the phase 2 study. Response rate was 20.8% (95% CI: 0.108–0.341), and the clinical benefit rate (CR + PR + SD) was 64.2%. Median time to disease progression was 4.6 months (95% CI: 2.79–6.18), median survival was 10.1 month (95% CI: 5.95–14.09, censorship = 20.75%), and 1-year survival was 41.0%. Common grade 3 or 4 adverse events (% of patients) were neutropenia (28.3%), fatigue (22.6%), and febrile neutropenia (9.4%). Conclusions: Twice-monthly gemcitabine and pemetrexed was well tolerated, with overall survival and clinical benefit indicating disease activity in NSCLC patients.

A retrospective analysis of outcomes across histological subgroups in a three-arm phase III trial of gemcitabine in combination with carboplatin or paclitaxel versus paclitaxel plus carboplatin for advanced non-small cell lung cancer

PURPOSE Three phase III trials have shown pemetrexed to be associated with improved clinical outcomes among patients with adenocarcinoma and large cell histology compared with patients with squamous histology in advanced non-small cell lung cancer (NSCLC). The current retrospective analysis examined whether differences were present by histology in a three-arm trial of gemcitabine-carboplatin (GCb) or gemcitabine-paclitaxel (GP) versus a standard regimen of paclitaxel-carboplatin (PCb). MATERIALS AND METHODS 1135 chemonaïve patients with stage IIIB or IV NSCLC were randomly allocated to receive: gemcitabine 1000 mg/m(2) days 1 and 8 plus carboplatin area under the curve (AUC) 5.5 day 1 (GCb); or gemcitabine 1000 mg/m(2) days 1 and 8 plus paclitaxel 200mg/m(2) day 1 (GP); or paclitaxel 225 mg/m(2) plus carboplatin AUC 6.0 day 1 (PCb). Cycles were repeated every 21 days up to 6 cycles or disease progression. Clinical results were retrospectively analyzed in by patient histology. RESULTS 202 patients (17.8%) had squamous, 555 (48.9%) had adenocarcinoma, 45 (4.0%) had large cell, and 333 (29.3%) had another histologic type. The overall response rate for squamous patients was greater than non-squamous (35.1% versus 27.8%, P=0.04). Median survival (9.5 months for squamous and 8.3 months for non-squamous) and median time to progression (5.0 months for squamous and 4.4 months for non-squamous) did not significantly vary by histologic group. For squamous histology, median survival was 6.6 months for GCb, 10.2 months for GP, and 10.3 months for PCb. For non-squamous disease, median survival was 8.2 months for GCb, 8.4 months for GP, and 8.3 months for PCb. A formal test for a histology-by-treatment interaction effect between GCb and PCb was significant (P=0.04). CONCLUSION In this trial of commonly used agents for advanced NSCLC, overall survival and time to progression were similar when comparing patients across histologies. The effect of treatment, however, varied across histologies.

Efficacy and safety of pemetrexed in elderly cancer patients: Results of an integrated analysis

PURPOSE To analyze pemetrexed in elderly patients (>or=65 years) based on data collected in three randomized, phase III registration trials. METHODS Patients who received pemetrexed as monotherapy or in combination with another drug were included in this analysis (N=764). In all studies, pemetrexed 500 mg/m(2) was administered every 21 days. Data from patients receiving pemetrexed were stratified by age +/-65 years. RESULTS Out of the 764 patients randomized, 271 were >or=65 years of age (35.4%). Of these, 28% had non-small cell lung cancer, 41% pancreatic cancer, and 31% had malignant pleural mesothelioma that was either locally advanced or metastatic. The overall response rate of the integrated database of elderly patients was 21.4%, with complete response in three patients (1.11% in >or=65 years vs. 1.01% in <65 years), partial response in 55 (20.30% vs. 19.68%), and stable disease in 116 (42.80% vs. 43.00%). Median survival time was 8.34 months in both groups, and median time to progressive disease was 4.80 months versus 4.60. Toxicity observed in the elderly group included 70 patients (25.8% vs. 17.0%; p=0.005) with grade 4 toxicity; myelosuppression was the major toxicity, with grade 3/4 neutropenia in 33% versus 22% (p<0.05), and thrombocytopenia in 13% versus 6% (p<0.05). Febrile neutropenia occurred in 4.8% versus 4.7% of patients. Non-hematological grade 3/4 events were fatigue (10.3% vs. 9.5%) and nausea (6.3% vs. 6.5%). CONCLUSIONS Pemetrexed produced similar treatment effects in older and younger patients, and appeared to be well tolerated in the elderly population. This analysis was limited by the pooling of different disease types and the lack of uniform treatment regimens.

A Comparison of White and African American Outcomes from a Three-Arm, Randomized, Phase III Multicenter Trial of Advanced or Metastatic Non-small Cell Lung Cancer

Purpose: To investigate the effect of race on the efficacy and safety of standard chemotherapy doublet regimens in African American patients, we conducted a subgroup analysis of a phase III randomized trial. Patients and Methods: Chemonaïve patients with a performance status of 0 or 1 and stage IIIB or IV non-small cell lung cancer were randomized to arm A: gemcitabine 1000 mg/m2 on days 1 and 8 plus carboplatin area under the curve 5.5 on day 1; arm B: the same schedule of gemcitabine plus paclitaxel 200 mg/m2 on day 1; or arm C: paclitaxel 225 mg/m2 on day 1 plus carboplatin area under the curve 6.0 on day 1. Cycles were repeated every 21 days up to 6. A site selection tool identified institutions with potential to recruit a minority population. Outcome and toxicity data of white and African American patients were compared. Results: Of 1135 total patients, 972 were white (85.6%) and 138 were African American (12.2%). Median survival was 8.3 months for white patients (95% confidence interval [CI]: 7.7–9.3) and 9.1 months for African American patients (95% CI: 8.2–11.1). Response rates were 29.1 and 29.0%, respectively. Rates of grade 3 or 4 toxicities were comparable. Among African Americans, median survival was 7.2 months (95% CI: 5.1–10.1) for gemcitabine-carboplatin (n = 47), 10.5 months (95% CI: 7.1–15.4) for gemcitabine-paclitaxel (n = 42), and 10.2 months (95% CI: 8.5–13.2) for paclitaxel-carboplatin (n = 49). Conclusion: Whites and African Americans had similar outcomes, although there was some variability in survival among African Americans across the three treatment groups.