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A modified version of the PGDx elioTM Plasma Resolve assay was validated as a laboratory-developed test (LDT) for clinical use in the Molecular Diagnostics Laboratory at Fox Chase Cancer Center. The test detects single nucleotide variants (SNVs) and small insertions and deletions (indels) in 33 target genes using fragmented genomic DNA extracted from plasma. The analytical performance of this assay was assessed with reference standard DNA and 29 samples from cancer patients and detected 66 SNVs and 23 indels. Using 50 ng of input DNA, the sensitivity was 95.5% to detect SNVs at 0.5% allele frequency, and the specificity was 92.3%. The sensitivity to detect indels at 1% allele frequency was 70.4%. A cutoff of 0.25% variant allele frequency (VAF) was set up for diagnostic reporting. An inter-laboratory study of concordance with an orthologous test resulted in a positive percent agreement (PPA) of 91.7%. [ABSTRACT FROM AUTHOR]

Abstract Background This phase I study investigates the feasibility of carboplatin plus dose-dense (q2-week) pemetrexed given concurrently with radiotherapy (XRT) for locally advanced and oligometastatic non-small cell lung cancer (NSCLC). Methods Eligible patients had Stage III or IV (oligometastatic) NSCLC. Patients received XRT to 63 Gy in standard fractionation. Patients received concurrent carboplatin (AUC = 6) during weeks 1 and 5 of XRT, and pemetrexed during weeks 1, 3, 5, and 7 of XRT. The starting dose level (level 1) of pemetrexed was 300 mg/m2. Following the finding of dose limiting toxicity (DLT) in dose level 1, an amended dose level (level 1A) continued pemetrexed at 300 mg/m2, but with involved field radiation instead of extended nodal irradiation. Consolidation consisted of carboplatin (AUC = 6) and pemetrexed (500 mg/m2) q3 weeks × 2 -3 cycles. Results Eighteen patients were enrolled. Fourteen patients are evaluable for toxicity analysis. Of the initial 6 patients treated on dose level 1, two experienced DLTs (one grade 4 sepsis, one prolonged grade 3 esophagitis). There was one DLT (grade 5 pneumonitis) in the 8 patients treated on dose level 1A. In 16 patients evaluable for response (4 with oligometastatic stage IV disease and 12 with stage III disease), the median follow-up time is 17.8 months. Thirteen of 16 patients had in field local regional response. The actuarial median survival time was 28.6 months in all patients and 34.7 months (estimated) in stage III patients. Conclusions Concurrent carboplatin with dose-dense (q2week) pemetrexed at 300 mg/m2 with involved field XRT is feasible and encouraging in patients with locally advanced and oligometastatic NSCLC. Trial Registration ClinicalTrials.gov NCT00330044

Abstract: Introduction: In a first-line study of advanced NSCLC, pemetrexed–cisplatin was more effective among patients with adenocarcinoma and large-cell carcinoma compared with gemcitabine–cisplatin (median survival of 11.8 versus 10.4 months, P =.005), while survival with pemetrexed–cisplatin was shorter than with gemcitabine–cisplatin in patients with squamous cell carcinoma. The comparability of pemetrexed–cisplatin to other commonly used regimens within histology subgroups needs to be explored. Methods: This retrospective analysis combined the patient-level data from three phase 3 randomized controlled trials that compared the efficacy of different third generation platinum- and non-platinum based doublets. Unadjusted median survival times and Cox covariate-adjusted treatment hazard ratio (HR) estimates were calculated. Overall results and subgroups by histological type were reported. Results: This combined analysis consisted of 3467 patients. In the overall analysis, adjusted HRs favored pemetrexed (HR <1.0) to each of the other 5 regimens, though none of these HRs were statistically significant. Among patients with non-squamous histology, pemetrexed–cisplatin produced favorable HRs to each of the other regimens, achieving statistical significance when compared with vinorelbine–cisplatin (HR=0.67; 95% confidence intervals [CI]: 0.50, 0.91) and gemcitabine–cisplatin (HR=0.85; 95% CI: 0.75, 0.97). Among patients with squamous histology, 4 of the 5 comparison regimens produced favorable HRs (HR >1.0) when compared with pemetrexed–cisplatin, with only the comparison with gemcitabine–cisplatin achieving statistical significance (HR=1.23; 95% CI: 1.00, 1.51). Conclusion: In the absence of randomized clinical trial data comparing pemetrexed–cisplatin to commonly used doublets in advanced NSCLC other than gemcitabine–cisplatin, this combined analysis of multiple trials provides estimates for such comparisons. [Copyright &y& Elsevier]

Background: This phase I study investigates the feasibility of carboplatin plus dose-dense (q2-week) pemetrexed given concurrently with radiotherapy (XRT) for locally advanced and oligometastatic non-small cell lung cancer (NSCLC). Methods: Eligible patients had Stage III or IV (oligometastatic) NSCLC. Patients received XRT to 63 Gy in standard fractionation. Patients received concurrent carboplatin (AUC = 6) during weeks 1 and 5 of XRT, and pemetrexed during weeks 1, 3, 5, and 7 of XRT. The starting dose level (level 1) of pemetrexed was 300 mg/m². Following the finding of dose limiting toxicity (DLT) in dose level 1, an amended dose level (level 1A) continued pemetrexed at 300 mg/m², but with involved field radiation instead of extended nodal irradiation. Consolidation consisted of carboplatin (AUC = 6) and pemetrexed (500 mg/m²) q3 weeks × 2 -3 cycles. Results: Eighteen patients were enrolled. Fourteen patients are evaluable for toxicity analysis. Of the initial 6 patients treated on dose level 1, two experienced DLTs (one grade 4 sepsis, one prolonged grade 3 esophagitis). There was one DLT (grade 5 pneumonitis) in the 8 patients treated on dose level 1A. In 16 patients evaluable for response (4 with oligometastatic stage IV disease and 12 with stage III disease), the median follow-up time is 17.8 months. Thirteen of 16 patients had in field local regional response. The actuarial median survival time was 28.6 months in all patients and 34.7 months (estimated) in stage III patients. Conclusions: Concurrent carboplatin with dose-dense (q2week) pemetrexed at 300 mg/m² with involved field XRT is feasible and encouraging in patients with locally advanced and oligometastatic NSCLC. Trial Registration: ClinicalTrials.gov NCT00330044 [ABSTRACT FROM AUTHOR]

Abstract: 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 1000mg/m2 days 1 and 8 plus carboplatin area under the curve (AUC) 5.5 day 1 (GCb); or gemcitabine 1000mg/m2 days 1 and 8 plus paclitaxel 200mg/m2 day 1 (GP); or paclitaxel 225mg/m2 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. [Copyright &y& Elsevier]

Objective tumor responses and survival rates with standard chemotherapy options for small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) have been disappointing. However, several promising new classes of agents have emerged in recent years, including the taxanes, mitotic spindle inhibitors, antimetabolites, and topoisomerase I and II inhibitors. The molecular target of several of these new agents is topoisomerase I, an enzyme that is essential for DNA replication and is up-regulated in tumor cells. Inhibition of this enzyme by drugs such as topotecan and irinotecan leads to cell death and is the basis for their anticancer activity. The process of DNA replication is halted by the covalent binding of the drug in a topoisomerase I drug/DNA ternary reaction intermediate. The pharmacokinetics of the approved regimen – a 30-min infusion daily for 5 days at 21-day intervals – are well defined, with proportional increases in the area under the plasma concentration-time curve, peak plasma concentration, and steady state concentration following application of higher doses. The antitumor activities of both the intravenous and oral formulations of topotecan have been tested in clinical trials. Topotecan is well tolerated and has demonstrated good efficacy in patients with relapsed SCLC when administered as monotherapy or in combination regimens as first-line or second-line therapy. Preliminary trials also indicate that topotecan is well tolerated and has activity in the first-line treatment of NSCLC. In this article an overview of new agents in lung cancer chemotherapy is provided, with particular attention paid to the topoisomerase I inhibitors. A review of topotecan – the first topoisomerase I inhibitor to be approved for second-line therapy in SCLC – is presented as an illustration of the promise these new agents hold for the treatment of SCLC and NSCLC.Copyright © 2001 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Previous studies in animals have demonstrated liposome-encapsulated doxorubicin (LED) has substantially less cardiac toxicity than free doxorubicin but retains antitumor activity. In a phase I clinical study of LED, the maximum tolerated dose was 90 mg/mand dose-limiting toxicity was considered to have been reached when granulocytopenia was produced. We used LED to treat 20 patients with advanced, measurable breast cancer. LED was given at doses of 60–75 mg/m every 3 weeks as an intravenous infusion. Regression of disease was objectively measured in nine patients; in five of these patients, complete regression of the index lesion occurred. The mean duration of the responses was 7 months. Hematologic toxicity consisted of grade 1–2 leukopenia in some patients. Gastrointestinal toxicity and mucositis were generally mild and tolerable. Alopecia occurred in all patients and usually was complete. Twelve patients received cumulative doses of LED of greater than 400 mg/m and were evaluated with radionuclide ventriculograms. In eight patients, the cumulative dose was greater than 500 mg/m, and five had endomyocardial biopsies. Four of these biopsy results were Billingham grade 0, while one (cumulative LED dose, 750 mg/m) showed grade 1 changes with mild myofibrillar loss and dilatation of the sarcoplasmic reticulum involving less than 5% of cardiac myocytes. Two patients had decreases in left ventricular ejection fraction. One of these patients had received a total dose of LED of 630 mg/m and had a decline of 13% in left ventricular ejection fraction, but had no clinical evidence of congestive heart failure and had a Billingham grade 0 endomyocardial biopsy. A second patient, who received a total dose of LED of 660 mg/m plus a 300-mg/m dose of free doxorubicin as adjuvant therapy more than a year prior to beginning LED treatment, had a decline of 17% in ejection fraction and developed congestive heart failure. An endomyocardial biopsy performed after failure developed showed Billingham grade 0 changes. These data show that LED has anti-tumor activity in patients with breast cancer and suggest that it is less cardio-toxic than free doxorubicin at cumulative doses of 500–880 mg/m. [J Natl Cancer Inst 82: 1706–1710, 1990] [ABSTRACT FROM PUBLISHER]

First-line treatment with a two-drug combination chemotherapy regimen comprising of a platinum-based agent with a third-generation agent has been the accepted standard of care in most countries for the treatment of advanced non-small-cell lung cancer (NSCLC). Previously, the addition of a third agent to standard chemotherapy regimens has failed to improve survival in the majority of randomized trials that have been conducted. However, recent findings suggest that the addition of the novel targeted agent bevacizumab to a standard paclitaxel/carboplatin regimen significantly improves survival. The addition of novel agents to gemcitabine-based regimens is therefore a logical approach to improving the treatment of advanced NSCLC. Several trials of gemcitabine-based regimens with bevacizumab are ongoing. [Copyright &y& Elsevier]

Objectives Due to the lack of direct head-to-head trials, there are limited data regarding the comparative effectiveness of induction-maintenance sequences. The objective of this study was to develop a cost-effectiveness model to compare induction-maintenance sequences in the US for the treatment of advanced non-squamous NSCLC. Materials and methods Decision analytic modelling was used to synthesize the treatment effect and baseline risk estimates for nine induction and maintenance treatment sequences, reflecting treatments used in the US. The model was structured using an area-under-the-curve approach and sensitivity analyses were conducted. Model validation was conducted by an independent third party. Results All active maintenance therapy-containing regimens, with the exception of gemcitabine + cisplatin (first-line) → erlotinib (maintenance), were more costly than induction-only regimens. Concerning treatments that may be cost effective, the incremental costs per life-year gained were $121,425, $148,994, and $191,270 for gemcitabine + cisplatin → erlotinib versus gemcitabine + cisplatin → best supportive care (BSC), pemetrexed + cisplatin → BSC versus gemcitabine + cisplatin → erlotinib, and for pemetrexed + cisplatin → pemetrexed versus pemetrexed + cisplatin → BSC, respectively. All other regimens were found to be dominated (carboplatin + paclitaxel → BSC; carboplatin + paclitaxel → erlotinib; carboplatin + paclitaxel → pemetrexed; bevacizumab + carboplatin + paclitaxel → bevacizumab) or extendedly dominated (cisplatin + gemcitabine → pemetrexed). Sensitivity analyses demonstrated stability. Conclusions Depending on the specific cost-effectiveness threshold used by a decision maker, the most cost-effective treatment sequence may include the referent comparator gemcitabine + cisplatin and the studied regimens of gemcitabine + cisplatin → erlotinib, pemetrexed + cisplatin → BSC, or pemetrexed + cisplatin → pemetrexed. [ABSTRACT FROM AUTHOR]

Current standard for locally advanced non-small cell lung cancer (NSCLC) is combined concurrent therapy with a platinum-based regimen. Preclinical synergistic activity of pemetrexed with radiation therapy (RT) and favorable toxicity profile has led to clinical trials evaluating pemetrexed in chemoradiation regimens. This literature search of concurrent pemetrexed and RT treatment of patients with stage III NSCLC included MEDLINE database, meeting abstracts, and the clinical trial registry database. Nineteen unique studies were represented across all databases including 11 phase I studies and eight phase II studies. Of the six phase II trials with mature data available, median overall survival ranged from 18.7 to 34 months. Esophagitis and pneumonitis occurred in 0–16% and 0–23% of patients, respectively. Of the ongoing trials, there is one phase III and four phase II trials with pemetrexed in locally advanced NSCLC. Pemetrexed can be administered safely at full systemic doses with either cisplatin or carboplatin concomitantly with radical doses of thoracic radiation therapy. While results from the ongoing phase III PROCLAIM trial are needed to address definitively the efficacy of pemetrexed–cisplatin plus RT in stage III NSCLC, available results from phase II trials suggest that this regimen has promising activity with an acceptable toxicity profile. [ABSTRACT FROM AUTHOR]

Background: There is a high unmet need for effective treatments for patients with squamous non-small cell lung cancer (NSCLC). Eli Lilly and Company is conducting a phase III, randomized, multicenter, open-label study of gemcitabine plus cisplatin plus necitumumab (GC + N) versus gemcitabine plus cisplatin (GC) for the first-line treatment of patients with stage IV squamous NSCLC. Given GC is not the only treatment commonly used for the treatment of squamous NSCLC, this study was designed to compare the survival, toxicity, and quality of life outcomes of current treatment strategies for squamous NSCLC in the first-line setting., Methods/design: A systematic review and meta-analysis (including indirect comparisons) of treatments used in squamous NSCLC will be conducted to assess the clinical efficacy (overall and progression-free survival), health-related quality of life (HRQoL), and safety (grade 3-4 toxicity) of GC + N compared to other treatments used in squamous NSCLC. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines will be followed for all aspects of this study. A systematic literature review will be conducted to identify randomized controlled trials evaluating chemotherapy treatment in first-line NSCLC. Eligible articles will be restricted to randomized controlled trials (RCTs) among chemotherapy-naïve advanced NSCLC cancer patients that report outcome data (survival, toxicity, or quality of life) for patients with squamous histology. Following data extraction and validation, data consistency and study heterogeneity will be assessed. A network meta-analysis will be conducted based on the available hazard ratios for overall and progression-free survival, odds ratios for published toxicity data, and mean difference of HRQoL scales. Sensitivity analyses will be conducted., Discussion: This is a presentation of the study protocol only. Results and conclusions are pending completion of this study., Systematic Review Registration: PROSPERO CRD42014008968.

Background: This phase I study investigates the feasibility of carboplatin plus dose-dense (q2-week) pemetrexed given concurrently with radiotherapy (XRT) for locally advanced and oligometastatic non-small cell lung cancer (NSCLC)., Methods: Eligible patients had Stage III or IV (oligometastatic) NSCLC. Patients received XRT to 63 Gy in standard fractionation. Patients received concurrent carboplatin (AUC = 6) during weeks 1 and 5 of XRT, and pemetrexed during weeks 1, 3, 5, and 7 of XRT. The starting dose level (level 1) of pemetrexed was 300 mg/m2. Following the finding of dose limiting toxicity (DLT) in dose level 1, an amended dose level (level 1A) continued pemetrexed at 300 mg/m2, but with involved field radiation instead of extended nodal irradiation. Consolidation consisted of carboplatin (AUC = 6) and pemetrexed (500 mg/m2) q3 weeks × 2 -3 cycles., Results: Eighteen patients were enrolled. Fourteen patients are evaluable for toxicity analysis. Of the initial 6 patients treated on dose level 1, two experienced DLTs (one grade 4 sepsis, one prolonged grade 3 esophagitis). There was one DLT (grade 5 pneumonitis) in the 8 patients treated on dose level 1A. In 16 patients evaluable for response (4 with oligometastatic stage IV disease and 12 with stage III disease), the median follow-up time is 17.8 months. Thirteen of 16 patients had in field local regional response. The actuarial median survival time was 28.6 months in all patients and 34.7 months (estimated) in stage III patients., Conclusions: Concurrent carboplatin with dose-dense (q2week) pemetrexed at 300 mg/m2 with involved field XRT is feasible and encouraging in patients with locally advanced and oligometastatic NSCLC.

Purpose: Gemcitabine plus carboplatin (GC) is active as front-line treatment for advanced non-small-cell lung cancer (NSCLC). For patients without progression, timing of second-line chemotherapy for optimum clinical benefit remains uncertain. This phase III, randomized trial assessed the efficacy and safety of docetaxel administered either immediately after GC or at disease progression., Patients and Methods: The chemotherapy-naïve patients enrolled had either stage IIIB NSCLC with pleural effusion or stage IV NSCLC. Gemcitabine (1,000 mg/m(2)) was administered on days 1 and 8 followed by carboplatin (area under the curve = 5) on day 1. After four 21-day cycles, patients who did not have progression were randomly assigned either to an immediate docetaxel group (docetaxel 75 mg/m(2) on day 1 every 21 days, with maximum of six cycles) or to a delayed docetaxel group. The primary end point was overall survival (OS) measured from random assignment. Additional analyses included tumor response, toxicity, progression-free survival (PFS), and quality of life (QOL)., Results: Enrollment totaled 566 patients; 398 patients completed GC; 309 patients were randomly assigned equally to the two docetaxel treatment groups. Toxicity profiles were generally comparable for the docetaxel groups. Median PFS for immediate docetaxel (5.7 months) was significantly greater (P = .0001) than for delayed docetaxel (2.7 months). Median OS for immediate docetaxel (12.3 months) was greater than for delayed docetaxel (9.7 months), but the difference was not statistically significant (P = .0853). QOL results were not statistically different (P = .76) between docetaxel groups., Conclusion: We observed a statistically significant improvement in PFS and a nonstatistically significant increase in OS when docetaxel was administered immediately after front-line GC, without increasing toxicity or decreasing QOL.