Helen Barraclough

Phase III, Open-Label, Randomized Study Comparing Concurrent Gemcitabine Plus Cisplatin and Radiation Followed by Adjuvant Gemcitabine and Cisplatin Versus Concurrent Cisplatin and Radiation in Patients With Stage IIB to IVA Carcinoma of the Cervix

PURPOSE To determine whether addition of gemcitabine to concurrent cisplatin chemoradiotherapy and as adjuvant chemotherapy with cisplatin improves progression-free survival (PFS) at 3 years compared with current standard of care in locally advanced cervical cancer. PATIENTS AND METHODS Eligible chemotherapy- and radiotherapy-naive patients with stage IIB to IVA disease and Karnofsky performance score ≥ 70 were randomly assigned to arm A (cisplatin 40 mg/m(2) and gemcitabine 125 mg/m(2) weekly for 6 weeks with concurrent external-beam radiotherapy [XRT] 50.4 Gy in 28 fractions, followed by brachytherapy [BCT] 30 to 35 Gy in 96 hours, and then two adjuvant 21-day cycles of cisplatin, 50 mg/m(2) on day 1, plus gemcitabine, 1,000 mg/m(2) on days 1 and 8) or to arm B (cisplatin and concurrent XRT followed by BCT only; dosing same as for arm A). RESULTS Between May 2002 and March 2004, 515 patients were enrolled (arm A, n = 259; arm B, n = 256). PFS at 3 years was significantly improved in arm A versus arm B (74.4% v 65.0%, respectively; P = .029), as were overall PFS (log-rank P = .0227; hazard ratio [HR], 0.68; 95% CI, 0.49 to 0.95), overall survival (log-rank P = .0224; HR, 0.68; 95% CI, 0.49 to 0.95), and time to progressive disease (log-rank P = .0012; HR, 0.54; 95% CI, 0.37 to 0.79). Grade 3 and 4 toxicities were more frequent in arm A than in arm B (86.5% v 46.3%, respectively; P < .001), including two deaths possibly related to treatment toxicity in arm A. CONCLUSION Gemcitabine plus cisplatin chemoradiotherapy followed by BCT and adjuvant gemcitabine/cisplatin chemotherapy improved survival outcomes with increased but clinically manageable toxicity when compared with standard treatment.

A Randomized Phase 3 Trial Comparing Pemetrexed/Carboplatin and Docetaxel/Carboplatin as First-Line Treatment for Advanced, Nonsquamous Non-small Cell Lung Cancer

Introduction: This study compared survival without toxicity in patients with advanced, nonsquamous non-small cell lung cancer who were treated with first-line pemetrexed/carboplatin or docetaxel/carboplatin. Methods: This multicenter, open-label, parallel-group, phase 3 trial comprised patients randomized (1:1) to pemetrexed/carboplatin (n = 128) or docetaxel/carboplatin (n = 132). Patients received treatment on day 1 of each 21-day cycle (maximum of six cycles). Treatment included carboplatin (area under the curve = 5 mg/ml × min) and pemetrexed (500 mg/m2) or docetaxel (75 mg/m2). The primary outcome measure, survival without treatment-emergent grade 3/4 toxicity, was defined as the time from randomization to the first treatment-emergent grade 3/4 adverse event or death and was analyzed using a log-rank test. The analysis population included 106 patients in the pemetrexed/carboplatin (Pem/Carb) group and 105 patients in the docetaxel/carboplatin (Doc/Carb) group. Results: Survival without treatment-emergent grade 3/4 toxicity was significantly longer in the Pem/Carb versus the Doc/Carb group (log-rank p < 0.001; median survival without treatment-emergent grade 3/4 toxicity: 3.2 versus 0.7 months; adjusted hazard ratio = 0.45 [95% confidence interval: 0.34–0.61]). Overall survival was similar in the Pem/Carb versus the Doc/Carb group (log-rank p = 0.934; median survival: 14.9 versus 14.7 months; adjusted hazard ratio = 0.93 [95% confidence interval: 0.66–1.32]). Compared with the Doc/Carb group, fewer patients in the Pem/Carb group experienced grade 3/4 drug-related, treatment-emergent neutropenia, leukopenia, or febrile neutropenia, and more patients experienced anemia and thrombocytopenia. There were three study drug-related deaths during treatment in each group. Conclusions: The favorable benefit-to-risk profile of pemetrexed/carboplatin suggests that pemetrexed/carboplatin is an appropriate first-line treatment option for chemonaïve patients with advanced, nonsquamous non-small cell lung cancer.

Biostatistics Primer: What a Clinician Ought to Know—Prognostic and Predictive Factors

Several prognostic factors in oncology have been established over the years, such as performance status, tumor size, and disease stage. The identification of prognostic and predictive factors is becoming increasingly important in medical research, particularly as scientific discoveries have led to better understanding of diseases and genetics, resulting in tailored therapy. Advances in drug discovery and better understanding of the mechanism of action, may also identify factors that may be prognostic and/or predictive. Prognostic or predictive factors may include patient characteristics such as age, ethnicity, sex, or smoking status, disease characteristics such as disease stage or nodal status, and molecular markers such as HER2 amplification and K ras mutation.It can be challenging to distinguish whether a factor is prognostic or predictive, based on what is reported in the literature. This article is intended to help the reader assess whether a factor is prognostic and/or predictive.

First-line pemetrexed plus cisplatin followed by gefitinib maintenance therapy versus gefitinib monotherapy in East Asian patients with locally advanced or metastatic non-squamous non-small cell lung cancer: a randomised, phase 3 trial.

BACKGROUND In the Iressa Pan-ASia Study (IPASS), gefitinib claimed improved progression-free survival (PFS) versus carboplatin-paclitaxel in clinically selected lung cancer patients. The primary objective of this study was to assess the PFS of pemetrexed-cisplatin (PC) followed by gefitinib maintenance versus gefitinib monotherapy in an IPASS-like population. METHODS In this open-label, randomised, phase 3 trial, eligible patients were ⩾18 years, chemonaïve, East Asian, light ex-smokers/never-smokers with advanced non-squamous non-small cell lung cancer, an Eastern Cooperative Oncology Group (ECOG) performance status 0-1 and unknown epidermal growth factor receptor (EGFR) mutation status who enrolled at 12 sites in Asia. Patients randomly received (1:1) pemetrexed (500 mg/m(2)) plus cisplatin (75mg/m(2)) for six 21-day cycles, followed by gefitinib maintenance or gefitinib monotherapy (250 mg/day). Patient tissue was retrospectively analysed for EGFR mutations. This study is registered with ClinicalTrials.gov, NCT01017874. FINDINGS Between 23rd November 2009 and 27th April 2012, 253 patients entered, and 236 patients were randomly assigned to and treated with PC therapy (N=114) and gefitinib monotherapy (N=118). Between-arm baseline characteristics were balanced. PFS was not significantly different between treatment arms (p=0.217). The unadjusted hazard ratio (HR) was 0.85 (95% confidence interval (CI) 0.63-1.13). The HR should be cautiously interpreted as it was not constant. EGFR mutation status was determined for 74 tissue samples; 50 (67.6%) had mutations. In a pre-specified subgroup analysis, only the treatment-by-EGFR mutation interaction was significant (p=0.008) for PFS. For the entire treatment period, a higher proportion of patients in the PC/gefitinib arm versus gefitinib experienced possibly drug-related grade 3-4 treatment-emergent adverse events (39 of 114 [34%] versus 19 of 118 [16%]; p=0.002). INTERPRETATION In the intention-to-treat (ITT) population, PFS was not significantly different. In the biomarker-assessable population, front-line EGFR tyrosine kinase inhibitor monotherapy was not efficacious in patients with wild-type EGFR. Identification of EGFR mutation status is key in the management of advanced non-squamous non-small cell lung cancer. FUNDING Eli Lilly and Company.

Smoking history as a predictive factor of treatment response in advanced non-small-cell lung cancer: a systematic review.

Recent trials in patients with advanced non-small-cell lung cancer (NSCLC) suggest that nonsmokers may benefit more from epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy than will smokers. The aim of this systematic review was to assess smoking history as a predictive factor for treatment outcomes in patients with NSCLC. Relevant published literature was identified through systematic searches of databases (MEDLINE, EMBASE, Cochrane Library), oncology and thoracic journals, and abstracts from major oncology conferences using prespecified criteria. Articles reporting treatment outcomes (overall survival [OS], progression-free survival [PFS], and/or response rate) in smoking history subgroups from randomized controlled trials of targeted therapy and/or chemotherapy were reviewed. Data from 30 trials (32 articles, 4 abstracts) were included. Of these, 23 trials tested first-line therapy. Treatment arms included EGFR TKIs (13 trials), EGFR monoclonal antibodies (2 trials), non-EGFR targeted treatments (9 trials), chemotherapy (27 trials), and placebo or best supportive care only (3 trials). Smoking history definitions and analyses of its effect on treatment outcomes varied widely. Only 11 trials reported testing for a treatment-by-smoking history interaction. The available evidence supports but does not confirm smoking history as a predictive factor for the response to TKIs, particularly in previously treated patients. The evidence does not support smoking history as a predictor of response to non-EGFR-targeted therapies or chemotherapy. Smoking history and its effect on treatment response are inadequately reported. More rigorous collection, analysis, and reporting may clarify whether smoking history is a predictor of treatment response in advanced NSCLC.

A Systematic Review of the Interobserver Variability for Histology in the Differentiation between Squamous and Nonsquamous Non-small Cell Lung Cancer

Introduction: The importance of identifying non-small cell lung cancer (NSCLC) histologic subtype has increased recently because of the development of target-specific chemotherapeutic agents. This systematic review was undertaken to examine the interobserver variability for histology in differentiating between subtypes of NSCLC, specifically the ability to differentiate squamous from nonsquamous histology. Methods: A systematic literature search was undertaken to identify studies that evaluated the reproducibility of histologic diagnosis by pathologists in their reporting of NSCLC subtypes. Studies were screened using a priori defined eligibility criteria. The National Health and Medical Research Council diagnostic levels of evidence were applied and quality assessed using the Quality Assessment of Diagnostic Accuracy Studies tool. Data were extracted and reanalyzed to permit comparison of agreement in nonsquamous and squamous cell carcinoma by 2 × 2 tables. Percentage agreement and kappa statistics were calculated for each included study. Results: Out of 1480 articles identified through the literature search, six were eligible for inclusion. The percentage agreement for all subtypes of NSCLC in the included studies ranged from 67.1 to 89.6% (&kgr;, 0.42–0.84). Based on the primary reanalysis of data (reanalysis 1), agreement between pathologists in differentiating nonsquamous and squamous histology ranged from 77.0 to 94.2% (&kgr; = 0.48–0.88) indicating a moderate to high level of agreement. Conclusion: The reasonably high agreement and kappa statistics for the included studies suggest that pathologists can reproducibly differentiate between nonsquamous and squamous NSCLC. This is clinically important in guiding oncologist decision making in choosing the most appropriate therapy for their patients.

Efficacy and safety of pemetrexed/cisplatin versus gemcitabine/cisplatin as first-line treatment in Chinese patients with advanced nonsquamous non-small cell lung cancer

OBJECTIVES Retrospective subgroup analysis in JMDB study indicates that the between-arm differences in overall survival (OS) in the East Asian subgroup were consistent with those observed in the entire JMDB study population. This bridging study (JMIL) further evaluated the efficacy and safety of first-line pemetrexed/cisplatin (PC) versus gemcitabine/cisplatin (GC) in Chinese patients with nonsquamous non-small cell lung cancer (NSCLC). The primary endpoint of this local registration trial was designed to compare OS in the combined dataset, consisting of Chinese patients in JMIL and 1252 nonsquamous patients in JMDB. MATERIALS AND METHODS Chinese patients with stage IIIB/IV nonsquamous NSCLC were randomly assigned (1:1) to 6 cycles maximum (21 days/cycle) of pemetrexed 500mg/m(2)+cisplatin 75mg/m(2) (day 1), or gemcitabine 1250mg/m(2) (days 1 and 8)+cisplatin 75mg/m(2) (day 1). RESULTS In JMIL, 256 Chinese patients were randomized (PC, n=126; GC, n=130). Patient baseline characteristics were balanced between treatment arms. In the combined dataset, PC was superior to GC in prolonging OS, with adjusted hazard ratio (HR) of 0.87 (95% CI: 0.77-0.98, p=0.023) and median OS of 11.76 versus 10.94 months. In the JMIL-only population, no significant OS difference observed between treatment arms (adjusted HR=1.03 [95% CI: 0.77-1.39, p=0.822]; unadjusted HR=0.996 [95% CI: 0.74-1.33, p=0.980]), nor for other secondary efficacy endpoints. Significantly fewer patients in the PC arm experienced drug-related grade 3/4 toxicities, 54 (43.2%) versus 71 (55.9%) for GC (p=0.045), with significantly lower rates of leukocytopenia, thrombocytopenia, and fatigue. CONCLUSION This study showed that in the combined population, OS of PC was superior to GC, while in the Chinese-only population, no significant difference was observed; a better safety and risk/benefit profile was found in the PC arm. A PC regimen should be considered as a standard of care in Chinese nonsquamous NSCLC patients in a first-line setting.

Histology as a treatment effect modifier in advanced non-small cell lung cancer: a systematic review of the evidence.

Background and objective:  We conducted a systematic review of prospective, randomized, controlled trials (RCT) to examine whether histology had a treatment modifying effect (TME) on the efficacy outcomes of chemotherapeutic agents in patients with advanced (stage IIIB‐IV) non‐small cell lung cancer (NSCLC).

Biostatistics Primer: What a Clinician Ought to Know: Hazard Ratios

Hazard ratios (HRs) are used commonly to report results from randomized clinical trials in oncology. However, they remain one of the most perplexing concepts for clinicians. A good understanding of HRs is needed to effectively interpret the medical literature to make important treatment decisions. This article provides clear guidelines to clinicians about how to appropriately interpret HRs. While this article focuses on the commonly used methods, the authors acknowledge that other statistical methods exist for analyzing survival data.

Biostatistics Primer: What a Clinician Ought to Know: Subgroup Analyses

Large randomized phase III prospective studies continue to redefine the standard of therapy in medical practice. Often when studies do not meet the primary endpoint, it is common to explore possible benefits in specific subgroups of patients. In addition, these analyses may also be done, even in the case of a positive trial to find subsets of patients where the therapy is especially effective or ineffective. These unplanned subgroup analyses are justified to maximize the information that can be obtained from a study and to generate new hypotheses. Unfortunately, however, they are too often overinterpreted or misused in the hope of resurrecting a failed study. It is important to distinguish these overinterpreted, misused, and unplanned subgroup analyses from those prespecified and well-designed subgroup analyses. This overview provides a practical guide to the interpretation of subgroup analyses.