Yingwei Qi

A Phase II Study of AT-101 (Gossypol) in Chemotherapy-Sensitive Recurrent Extensive-Stage Small Cell Lung Cancer

Background: AT-101 is an oral inhibitor of the antiapoptotic Bcl proteins (Bcl-2, Bcl-XL, Bcl-W, and Mcl-1) and an inducer of the pro-apoptotic proteins noxa and puma. We studied the efficacy of AT-101 in patients with recurrent chemosensitive extensive-stage small cell lung cancer (SCLC). Methods: Patients with recurrent “sensitive” SCLC (defined as no progression during and no disease recurrence <2 months after completion of first-line platinum-based chemotherapy) were eligible. AT-101 was administered 20 mg orally daily for 21 of 28 days each cycle for up to six cycles. The primary end point was the objective response rate. Results: At the time of planned interim evaluation, none of the 14 evaluable patients enrolled in the first stage had any response to therapy, and the study was closed permanently for further accrual. Three patients (21%) achieved stable disease after two cycles of therapy. Grade 3 toxicities included anorexia, fatigue, and nausea/vomiting. Conclusions: AT-101 is not active in patients with recurrent chemosensitive SCLC.

Tumor response and progression-free survival as potential surrogate endpoints for overall survival in extensive stage small-cell lung cancer: findings on the basis of North Central Cancer Treatment Group trials.

The authors investigated the putative surrogate endpoints of best response, complete response (CR), confirmed response, and progression‐free survival (PFS) for associations with overall survival (OS), and as possible surrogate endpoints for OS.

Tumor response and progression-free survival as potential surrogate endpoints for overall survival in extensive stage small-cell lung cancer

The authors investigated the putative surrogate endpoints of best response, complete response (CR), confirmed response, and progression‐free survival (PFS) for associations with overall survival (OS), and as possible surrogate endpoints for OS.

Pretreatment Quality of Life Is an Independent Prognostic Factor for Overall Survival in Patients with Advanced Stage Non-small Cell Lung Cancer

Hypothesis: We conducted this pooled analysis to assess the prognostic value of pretreatment Quality of Life (QOL) assessments on overall survival (OS) in advanced non-small cell lung cancer (NSCLC). Methods: Four hundred twenty patients with advanced NSCLC (stages IIIB with pleural effusion and IV) from six North Central Cancer Treatment Group trials were included in this study. QOL assessments included the single-item Uniscale (355 patients), Lung Cancer Symptom Scale (217 patients), and Functional Assessment of Cancer Therapy-Lung (197 patients). QOL scores were transformed to a 0 to 100 scale with higher scores representing better status and categorized using the sample median or clinically deficient score (CDS, ≤50 versus >50). Cox proportional hazards models stratified by study were used to evaluate the prognostic importance of QOL on OS alone and in the presence of other prognostic factors such as performance status, age, gender, body mass index, and laboratory parameters. Results: Pretreatment QOL accessed by Uniscale was significantly associated with OS univariately (p < 0.0001). Uniscale (p < 0.0001; hazard ratio = 1.6 for the sample median and 2.0 for the CDS categorization) and body mass index were the only significant predictors of OS multivariately. The median survival of patients who had a Uniscale score less than or equal to the CDS (≤50) was 5.7 versus 11.1 months for the >50 group; and 7.8 versus 13 months for the less than or equal to sample median (≤83) group and >83 group, respectively. The Lung Cancer Symptom Scale and the Functional Assessment of Cancer Therapy-Lung total scores were not significant predictors of OS. Conclusions: Pretreatment QOL measured by Uniscale is a significant and an independent prognostic factor for OS, and QOL should be routinely integrated as a stratification factor in advanced NSCLC trials.

Endpoints in phase II trials for advanced non-small cell lung cancer.

Introduction: We investigated the relationships between progression-free survival (PFS), response, confirmed response, and failure-free survival (FFS) with overall survival (OS) to assess their suitability as primary endpoints in phase II trials for advanced non-small cell lung cancer. Methods: Individual data of 284 patients from four phase II trials were pooled. Progression status and response were modeled as time dependent variables in a multivariable (adjusted for baseline age, gender, stage, and performance status) Cox proportional hazards model for OS, stratified by trial. Subsequently, Cox proportional hazards models were used to assess the impact of PFS, response, confirmed response, and FFS on subsequent survival, using landmark analysis at 8, 12, 16, 20, and 24 weeks. Model discrimination was evaluated using the concordance index (c-index). Results: The overall median OS, PFS, and FFS were 9.6, 3.7, and 2.8 months, and the response and confirmed response rates were 21 and 15%, respectively. Both progression status and response as time dependent covariates were significantly associated with OS (p < 0.0001; p = 0.009). PFS and FFS at 12 weeks significantly predicted for subsequent survival with the strongest c-index and hazard ratio combination in landmark analyses (hazard ratio, c-index: PFS: 0.39, 0.67; FFS: 0.37, 0.67). The c-indices for response and confirmed response were low (0.59–0.60), indicating their inability to sufficiently discriminate subsequent patient survival outcomes. Conclusions: FFS or PFS at 12 weeks is a stronger predictor of subsequent patient survival compared with tumor response and should be routinely used as endpoints in phase II trials for advanced non-small cell lung cancer.

Alpha1-antitrypsin deficiency carriers, serum alpha 1-antitrypsin concentration, and non-small cell lung cancer survival.

Introduction: Although the association between alpha 1-antitrypsin deficiency (&agr;1ATD) carriers and lung cancer risk has been found, the effects of &agr;1ATD carriers and serum alpha 1-antitrypsin (&agr;1AT) concentration on non-small cell lung cancer (NSCLC) survival remained unclear. Methods: Patients were selected from the Epidemiology and Genetics of Lung Cancer Study at Mayo Clinic with the criteria of (1) primary NSCLC diagnosis and (2) available &agr;1ATD carrier status tested by isoelectric focusing serum &agr;1AT concentration by immunonephelometry. The effects of carrier status and serum &agr;1AT concentration on survival were evaluated by Cox proportional hazards models with (1) a landmark approach, where overall survival was defined from the time of blood draw to death from any cause and (2) included only patients with blood draw time before initial treatment. Results: One thousand three hundred twenty-one patients were included in this study, with 179 &agr;1ATD carriers and 1142 noncarriers. No differences in overall survival by &agr;1ATD carrier status were found (adjusted hazard ratio [AHR]: 0.98; 95% confidence interval [CI]: 0.82–1.18). Nevertheless, serum &agr;1AT concentration was significantly associated with survival among all patients in the landmark model (AHR per 50 mg/dl increments: 1.15; 95% CI: 1.10–1.20) and among patients whose blood was drawn for serum &agr;1AT level assessment before any treatment (AHR per 50 mg/dl increments: 1.44; 95% CI: 1.21–1.71). Conclusions: Being an &agr;1ATD carrier had no significant effect on NSCLC survival. The increased serum &agr;1AT concentration was a poor prognosis marker for NSCLC, regardless of carrier status.

Impact of disease progression date determination on progression-free survival estimates in advanced lung cancer†‡

In patients with advanced lung cancer, overall survival is largely influenced by progression status. Because progression‐free survival (PFS)‐based endpoints are controversial, the authors evaluated the impact of the progression date (PD) determination approach on PFS estimates.

NCCTG N0821 (Alliance): A Phase II First-Line Study of Pemetrexed, Carboplatin, and Bevacizumab in Elderly Patients with Advanced Nonsquamous Non–Small-Cell Lung Cancer With Good Performance Status

Background: We hypothesized that the combination of bevacizumab, carboplatin, and pemetrexed will be an effective first-line regimen in fit, elderly patients with nonsquamous non–small-cell lung cancer. Methods: Treatment-naïve, stage IIIB/IV nonsquamous non–small-cell lung cancer patients more than 70 years old with good performance status (Eastern Cooperative Oncology Group performance status 0–1) and adequate organ function were eligible. Carboplatin area under the curve 6, pemetrexed 500 mg/m2, and bevacizumab 15 mg/kg were administered on day 1 of each 21-day cycle (up to six cycles) followed by maintenance pemetrexed and bevacizumab. The primary end point of 6-month progression-free survival rate of at least 70% was assessed using a one-stage binomial design. Quality of life (QOL) questionnaires were administered. Polymorphisms in genes encoding relevant proteins (drug targets, transport, and metabolism proteins) were correlated with treatment outcome. Results: Fifty-seven eligible patients were enrolled. Median age was 74.5 years. Median treatment cycles received was 6. The most common grade 3 or higher non-hematologic adverse events were fatigue (26%) and hypertension (11%); 16% had grade 4 neutropenia and 6.5% had grade 4 thrombocytopenia. Three patients experienced grade 3/4 hemorrhagic events (one pulmonary, two gastrointestinal). Primary end point of PFS6 was 60% (95% confidence interval [CI]: 45.9–73%). Median PFS was 7.0 months (95% CI: 5.9–10.1), median overall survival was 13.7 months (95% CI: 9.4–16.8). Polymorphic KDR and VEGFA variants correlated with survival and toxicity, respectively. There was no significant change in overall QOL scores over time. Conclusion: This regimen is feasible and did not decrease the QOL in this study population. However, it did not meet the primary efficacy end point.

The purported effects of alcohol on appetite and weight in lung cancer patients.

Loss of appetite and weight predict poor outcomes in patients with advanced cancer. Effective and affordable palliative strategies are lacking; but because an emerging non-cancer literature suggests that alcohol can increase appetite and weight, this study explored associations between alcohol and clinical outcomes in lung cancer patients. Among 404 consecutive lung cancer patients enrolled in the Mayo Clinic Lung Cancer Cohort between 2004 and 2008, alcohol consumption (within 6 mo of diagnosis) was as follows: 199 (49%) used none, 158 (14%) were moderate users (7 drinks per wk or less), and 47 (12%) were heavier consumers (more than 7 drinks per wk). Only heavier consumers had a lower likelihood of anorexia (odds ratio: 0.49; 95% CI: 0.25, 0.94; P = 0.03) and weight loss (odds ratio: 0.43; 95% CI: 0.20, 0.91; P = 0.03) compared to those who consumed no alcohol. These conclusions were sustained in multivariate analyses. Neither moderate nor heavier consumption was associated with better or worse survival, although, in univariate analyses, a drop in alcohol consumption was associated with worse survival. This report suggests a need for further study of alcohol as a palliative agent for cancer-associated loss of appetite and weight.

Tumor Response and Progression-Free Survival as Potential Surrogate Endpoints for Overall Survival in Extensive-Stage Small Cell Lung Cancer (ES-SCLC): Findings Based on North Central Cancer Treatment Group (NCCTG) Trials

The authors investigated the putative surrogate endpoints of best response, complete response (CR), confirmed response, and progression‐free survival (PFS) for associations with overall survival (OS), and as possible surrogate endpoints for OS.