150 results on '"Woll PJ"'
Search Results
2. Phase II trial of temozolomide in low-grade non-Hodgkin's lymphoma
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Woll, PJ, primary, Crowther, D, additional, Johnson, PWM, additional, Soukop, M, additional, Harper, PG, additional, Harris, M, additional, Brampton, MH, additional, and Newlands, ES, additional
- Published
- 1995
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3. Peripheral blood progenitor cell transplantation in lymphoma and leukemia using a single apheresis
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Pettengell, R, primary, Morgenstern, GR, additional, Woll, PJ, additional, Chang, J, additional, Rowlands, M, additional, Young, R, additional, Radford, JA, additional, Scarffe, JH, additional, Testa, NG, additional, and Crowther, D, additional
- Published
- 1993
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4. A phase I study of intravenous bryostatin 1 in patients with advanced cancer
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Prendiville, J, primary, Crowther, D, additional, Thatcher, N, additional, Woll, PJ, additional, Fox, BW, additional, McGown, A, additional, Testa, N, additional, Stern, P, additional, McDermott, R, additional, Potter, M, additional, and Pettit, GR, additional
- Published
- 1993
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5. Cytokine Therapy
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Woll, PJ, primary
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- 1993
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6. Use of rHuG-CSF (lenograstim) to dose intensify in small cell lung cancer (SCLC): A randomised study
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Woll, PJ, primary, Hodgetts, J, additional, Lomax, L, additional, and Thatcher, N, additional
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- 1993
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7. Overall survival improvement in patients with lung cancer and bone metastases treated with denosumab versus zoledronic acid: subgroup analysis from a randomized phase 3 study.
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Scagliotti GV, Hirsh V, Siena S, Henry DH, Woll PJ, Manegold C, Solal-Celigny P, Rodriguez G, Krzakowski M, Mehta ND, Lipton L, García-Sáenz JA, Pereira JR, Prabhash K, Ciuleanu TE, Kanarev V, Wang H, Balakumaran A, Jacobs I, and Scagliotti, Giorgio Vittorio
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- 2012
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8. Randomized double-blind placebo-controlled trial of thalidomide in combination with gemcitabine and Carboplatin in advanced non-small-cell lung cancer.
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Lee SM, Rudd R, Woll PJ, Ottensmeier C, Gilligan D, Price A, Spiro S, Gower N, Jitlal M, and Hackshaw A
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- 2009
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9. Overcoming CYP1A1/1A2 mediated induction of metabolism by escalating erlotinib dose in current smokers.
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Hughes AN, O'Brien ME, Petty WJ, Chick JB, Rankin E, Woll PJ, Dunlop D, Nicolson M, Boinpally R, Wolf J, Price A, Hughes, Andrew N, O'Brien, Mary E R, Petty, W Jeffrey, Chick, Jonathan B, Rankin, Elaine, Woll, Penella J, Dunlop, David, Nicolson, Marianne, and Boinpally, Ramesh
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- 2009
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10. Neuropeptide growth factors and cancer
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Woll, PJ, primary
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- 1991
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11. Treatment of bone metastases from breast cancer with (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (APD).
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Coleman, RE, Woll, PJ, Miles, M, Scrivener, W, Rubens, RD, Coleman, R E, Woll, P J, and Rubens, R D
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- 1988
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12. Bombesin and bombesin antagonists: Studies in Swiss 3T3 cells and human small cell lung cancer*.
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Woll, PJ and Rozengurt, E
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- 1988
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13. Bombesin and bombesin antagonists: Studies in Swiss 3T3 cells and human small cell lung cancer*
- Author
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Woll, PJ and Rozengurt, E
- Abstract
Bombesins are potent growth factors for murine Swiss 3T3 cells. Using these cells in chemically defined conditions we have been able to characterise the bombesin receptor and the early signals preceding DNA synthesis. We describe two substance P analogues [DArg1, DPro2, DTrp7,9, Leu11] substance P and [DArg1, DPhe5, DTrp7,9, Leu11] substance P which competitively block the binding of bombesins to their receptor and all the events leading to mitogenesis. Bombesins are secreted by human small cell lung cancers (SCLC) and may act as autocrine growth factors for these tumours, so the development of peptide bombesin antagonists could have therapeutic implications. We demonstrate that the antagonists can reversibly inhibit the growth of SCLC in vitro, with relatively little effect on other lung tumours.
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- 1988
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14. INTERFERONS IN ONCOLOGY
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Woll, PJ and Pettengell, R
- Abstract
SUMMARYThe interferons are natural glycoproteins secreted in response to various stimuli, including viral infection. They have antiviral, antiproliferative and immunomodulatory effects on different target cell populations. Since recombinant human interferons have become available, they have been tested in a wide range of malignancies. They are well established in the treatment of hairy cell leukaemia, chronic myelogenous leukaemia and multiple myeloma. Although they have documented activity against lymphoma, melanoma, renal cell cancer and carcinoid tumours, their role in the treatment of these tumours is less clear. In the common solid tumours, such as lung cancer and colorectal cancer, the use of interferons remains experimental. Here we will summarise their practice applications in oncology, using randomised studies where available to establish their place in multi‐modality treatment. We will not discuss their use as antiviral or immunomodulating agents in viral and autoimmune diseases, multiple sclerosis or after organ transplantation.
- Published
- 1997
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15. Effects of COX-2 inhibition on expression of vascular endothelial growth factor and interleukin-8 in lung cancer cells.
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Zhu YM, Azahri NS, Yu DC, Woll PJ, Zhu, Yong Ming, Azahri, Nor Saadah M, Yu, Danny C W, and Woll, Penella J
- Abstract
Background: Cyclooxygenase (COX)-2 has been implicated in tumour progression, angiogenesis and metastasis in non-small cell lung cancer (NSCLC). We speculated that inhibition of COX-2 activity might reduce expression of the pro-angiogenic factors vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) in lung cancer cells.Methods: The levels of IL-8, VEGF and prostaglandin E2 (PGE2) were measured by ELISA. Expression of COX-1 and COX-2 was determined by Western blotting. Inhibition or knockdown of COX-2 was achieved by treating NSCLC cells with specific COX-2 inhibitor NS-398 or COX-2 siRNA, respectively.Results: We found that NSCLC cell lines produced more IL-8 than VEGF (p < 0.001). In contrast, small cell lung cancer (SCLC) cell lines produced more VEGF than IL-8 (p < 0.001). COX-1 was expressed in all cell lines, but COX-2 was expressed only in NSCLC cell lines. Consistent with this, PGE2 was significantly higher in NSCLC cell lines than SCLC cell lines (p < 0.001). We tested these cell lines with a potent specific COX-2 inhibitor NS-398 at concentrations of 0.02, 0.2, 2, 20 microM for 24 or 48 h. The COX-2 activity was reduced in a dose-dependent fashion as shown by reduced PGE2 production. VEGF was significantly reduced following the treatment of NS-398 in A549 (by 31%) and MOR/P (by 47%) cells lines which expressing strong COX-2, but not in H460 cell line which expressing very low COX-2. However, IL-8 was not reduced in these cell lines. To confirm these results, we knocked down COX-2 expression with COX-2 siRNA in these cell lines. VEGF was significantly decreased in A549 (by 24%) and in MOR/P (by 53%), but not in H460 whereas IL-8 was not affected in any cell line.Conclusion: We conclude that NSCLC cells produce much higher levels of IL-8 than SCLC cells whereas both NSCLC and SCLC cells produce similar levels of VEGF. COX-2 is only expressed in NSCLC cells, but not in SCLC cells. VEGF is produced in both NSCLC and SCLC cells regardless of COX-2 expression. However, VEGF production is, at least partly, COX-2 dependent in NSCLC cells expressing COX-2. In contrast, IL-8 production is COX-2 independent in both NSCLC and SCLC cells. We speculate that combined targeting of COX-2 and IL-8 may be useful in the treatment of patients with NSCLC and targeting VEGF may be useful in the treatment of patients with SCLC. [ABSTRACT FROM AUTHOR]- Published
- 2008
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16. A phase II nonrandomised open-label study of liposomal daunorubicin (DaunoXome) in advanced soft tissue sarcoma.
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McTiernan A, Whelan J, Leahy M, Woll PJ, and Judson I
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- 2006
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17. Relative hypocalcaemia and muscle cramps in patients receiving imatinib for gastrointestinal stromal tumour.
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Zekri JM, Robinson MH, and Woll PJ
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- 2006
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18. Identification of genetically predicted DNA methylation markers associated with non-small cell lung cancer risk among 34,964 cases and 448,579 controls.
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Zhao X, Yang M, Fan J, Wang M, Wang Y, Qin N, Zhu M, Jiang Y, Gorlova OY, Gorlov IP, Albanes D, Lam S, Tardón A, Chen C, Goodman GE, Bojesen SE, Landi MT, Johansson M, Risch A, Wichmann HE, Bickeböller H, Christiani DC, Rennert G, Arnold SM, Brennan P, Field JK, Shete S, Le Marchand L, Liu G, Hung RJ, Andrew AS, Kiemeney LA, Zienolddiny S, Grankvist K, Johansson M, Caporaso NE, Woll PJ, Lazarus P, Schabath MB, Aldrich MC, Patel AV, Davies MPA, Ma H, Jin G, Hu Z, Amos CI, Shen H, and Dai J
- Subjects
- Adult, Humans, DNA Methylation, Genome-Wide Association Study, Epigenesis, Genetic, Biomarkers, CpG Islands, Carcinoma, Non-Small-Cell Lung genetics, Lung Neoplasms genetics
- Abstract
Background: Although the associations between genetic variations and lung cancer risk have been explored, the epigenetic consequences of DNA methylation in lung cancer development are largely unknown. Here, the genetically predicted DNA methylation markers associated with non-small cell lung cancer (NSCLC) risk by a two-stage case-control design were investigated., Methods: The genetic prediction models for methylation levels based on genetic and methylation data of 1595 subjects from the Framingham Heart Study were established. The prediction models were applied to a fixed-effect meta-analysis of screening data sets with 27,120 NSCLC cases and 27,355 controls to identify the methylation markers, which were then replicated in independent data sets with 7844 lung cancer cases and 421,224 controls. Also performed was a multi-omics functional annotation for the identified CpGs by integrating genomics, epigenomics, and transcriptomics and investigation of the potential regulation pathways., Results: Of the 29,894 CpG sites passing the quality control, 39 CpGs associated with NSCLC risk (Bonferroni-corrected p ≤ 1.67 × 10
-6 ) were originally identified. Of these, 16 CpGs remained significant in the validation stage (Bonferroni-corrected p ≤ 1.28 × 10-3 ), including four novel CpGs. Multi-omics functional annotation showed nine of 16 CpGs were potentially functional biomarkers for NSCLC risk. Thirty-five genes within a 1-Mb window of 12 CpGs that might be involved in regulatory pathways of NSCLC risk were identified., Conclusions: Sixteen promising DNA methylation markers associated with NSCLC were identified. Changes of the methylation level at these CpGs might influence the development of NSCLC by regulating the expression of genes nearby., Plain Language Summary: The epigenetic consequences of DNA methylation in lung cancer development are still largely unknown. This study used summary data of large-scale genome-wide association studies to investigate the associations between genetically predicted levels of methylation biomarkers and non-small cell lung cancer risk at the first time. This study looked at how well larotrectinib worked in adult patients with sarcomas caused by TRK fusion proteins. These findings will provide a unique insight into the epigenetic susceptibility mechanisms of lung cancer., (© 2023 American Cancer Society.)- Published
- 2024
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19. Axitinib in patients with advanced/metastatic soft tissue sarcoma (Axi-STS): an open-label, multicentre, phase II trial in four histological strata.
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Woll PJ, Gaunt P, Gaskell C, Young R, Benson C, Judson IR, Seddon BM, Marples M, Ali N, Strauss SJ, Lee A, Hughes A, Kaur B, Hughes D, and Billingham L
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- Humans, Axitinib adverse effects, Vascular Endothelial Growth Factor A, Angiogenesis Inhibitors therapeutic use, Treatment Outcome, Leiomyosarcoma drug therapy, Sarcoma, Synovial chemically induced, Sarcoma, Synovial drug therapy, Hemangiosarcoma chemically induced, Hemangiosarcoma drug therapy, Sarcoma drug therapy, Soft Tissue Neoplasms drug therapy, Soft Tissue Neoplasms pathology
- Abstract
Background: Axitinib is an oral vascular endothelial growth factor receptor inhibitor with anti-tumour activity in renal, thyroid, and pancreatic cancer., Methods: Axi-STS was a pathologically-stratified, non-randomised, open-label, multi-centre, phase II trial of continuous axitinib treatment in patients ≥16 years, performance status ≤2, with pathologically-confirmed advanced/metastatic soft tissue sarcoma (STS). Patients were recruited within four tumour strata, each analysed separately: angiosarcoma, leiomyosarcoma, synovial sarcoma, or other eligible STSs. The primary outcome was progression-free survival at 12 weeks (PFS12). A Simon's two-stage design with activity defined as PFS12 rate of 40% determined a sample size of 33 patients per strata., Results: Between 31-August-2010 and 29-January-2016, 145 patients were recruited: 38 angiosarcoma, 37 leiomyosarcoma, 36 synovial sarcoma, and 34 other subtypes. PFS12 rate for each stratum analysed was 42% (95% lower confidence interval (LCI); 29), 45% (95% LCI; 32), 57% (95% LCI; 42), and 33% (95% LCI; 21), respectively. There were 74 serious adverse events including two treatment-related deaths of pulmonary haemorrhage and gastrointestinal bleeding. Fatigue and hypertension were the most common grade 3 adverse events., Conclusions: Axitinib showed clinical activity in all STS strata investigated. The adverse event profile was acceptable, supporting further investigation in phase III trials., Clinical Trial Registration: ISRCTN 60791336., (© 2023. The Author(s).)
- Published
- 2023
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20. Candidate pathway analysis of surfactant proteins identifies CTSH and SFTA2 that influences lung cancer risk.
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Luyapan J, Bossé Y, Li Z, Xiao X, Rosenberger A, Hung RJ, Lam S, Zienolddiny S, Liu G, Kiemeney LA, Chen C, McKay J, Johansson M, Johansson M, Tardon A, Fernandez-Tardon G, Brennan P, Field JK, Davies MP, Woll PJ, Cox A, Taylor F, Arnold SM, Lazarus P, Grankvist K, Landi MT, Christiani DC, MacKenzie TA, and Amos CI
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- Humans, Genome-Wide Association Study, Lung metabolism, Genotype, Surface-Active Agents metabolism, Polymorphism, Single Nucleotide, Genetic Predisposition to Disease, Cathepsin H genetics, Cathepsin H metabolism, Lung Neoplasms, Pulmonary Surfactants metabolism
- Abstract
Pulmonary surfactant is a lipoprotein synthesized and secreted by alveolar type II cells in lung. We evaluated the associations between 200,139 single nucleotide polymorphisms (SNPs) of 40 surfactant-related genes and lung cancer risk using genotyped data from two independent lung cancer genome-wide association studies. Discovery data included 18,082 cases and 13,780 controls of European ancestry. Replication data included 1,914 cases and 3,065 controls of European descent. Using multivariate logistic regression, we found novel SNPs in surfactant-related genes CTSH [rs34577742 C > T, odds ratio (OR) = 0.90, 95% confidence interval (CI) = 0.89-0.93, P = 7.64 × 10-9] and SFTA2 (rs3095153 G > A, OR = 1.16, 95% CI = 1.10-1.21, P = 1.27 × 10-9) associated with overall lung cancer in the discovery data and validated in an independent replication data-CTSH (rs34577742 C > T, OR = 0.88, 95% CI = 0.80-0.96, P = 5.76 × 10-3) and SFTA2 (rs3095153 G > A, OR = 1.14, 95% CI = 1.01-1.28, P = 3.25 × 10-2). Among ever smokers, we found SNPs in CTSH (rs34577742 C > T, OR = 0.89, 95% CI = 0.85-0.92, P = 1.94 × 10-7) and SFTA2 (rs3095152 G > A, OR = 1.20, 95% CI = 1.14-1.27, P = 4.25 × 10-11) associated with overall lung cancer in the discovery data and validated in the replication data-CTSH (rs34577742 C > T, OR = 0.88, 95% CI = 0.79-0.97, P = 1.64 × 10-2) and SFTA2 (rs3095152 G > A, OR = 1.15, 95% CI = 1.01-1.30, P = 3.81 × 10-2). Subsequent transcriptome-wide association study using expression weights from a lung expression quantitative trait loci study revealed genes most strongly associated with lung cancer are CTSH (PTWAS = 2.44 × 10-4) and SFTA2 (PTWAS = 2.32 × 10-6)., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2023
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21. Gene-gene interaction of AhRwith and within the Wntcascade affects susceptibility to lung cancer.
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Rosenberger A, Muttray N, Hung RJ, Christiani DC, Caporaso NE, Liu G, Bojesen SE, Le Marchand L, Albanes D, Aldrich MC, Tardon A, Fernández-Tardón G, Rennert G, Field JK, Davies MPA, Liloglou T, Kiemeney LA, Lazarus P, Wendel B, Haugen A, Zienolddiny S, Lam S, Schabath MB, Andrew AS, Duell EJ, Arnold SM, Goodman GE, Chen C, Doherty JA, Taylor F, Cox A, Woll PJ, Risch A, Muley TR, Johansson M, Brennan P, Landi MT, Shete SS, Amos CI, and Bickeböller H
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- Basic Helix-Loop-Helix Transcription Factors metabolism, Female, Genotype, Humans, Lung Neoplasms metabolism, Male, Middle Aged, Receptors, Aryl Hydrocarbon metabolism, Wnt Signaling Pathway, Basic Helix-Loop-Helix Transcription Factors genetics, Gene Expression Regulation, Neoplastic, Genetic Predisposition to Disease, Genome-Wide Association Study methods, Lung Neoplasms genetics, RNA, Neoplasm genetics, Receptors, Aryl Hydrocarbon genetics
- Abstract
Background: Aberrant Wnt signalling, regulating cell development and stemness, influences the development of many cancer types. The Aryl hydrocarbon receptor (AhR) mediates tumorigenesis of environmental pollutants. Complex interaction patterns of genes assigned to AhR/Wnt-signalling were recently associated with lung cancer susceptibility., Aim: To assess the association and predictive ability of AhR/Wnt-genes with lung cancer in cases and controls of European descent., Methods: Odds ratios (OR) were estimated for genomic variants assigned to the Wnt agonist and the antagonistic genes DKK2, DKK3, DKK4, FRZB, SFRP4 and Axin2. Logistic regression models with variable selection were trained, validated and tested to predict lung cancer, at which other previously identified SNPs that have been robustly associated with lung cancer risk could also enter the model. Furthermore, decision trees were created to investigate variant × variant interaction. All analyses were performed for overall lung cancer and for subgroups., Results: No genome-wide significant association of AhR/Wnt-genes with overall lung cancer was observed, but within the subgroups of ever smokers (e.g., maker rs2722278 SFRP4; OR = 1.20; 95% CI 1.13-1.27; p = 5.6 × 10
-10 ) and never smokers (e.g., maker rs1133683 Axin2; OR = 1.27; 95% CI 1.19-1.35; p = 1.0 × 10-12 ). Although predictability is poor, AhR/Wnt-variants are unexpectedly overrepresented in optimized prediction scores for overall lung cancer and for small cell lung cancer. Remarkably, the score for never-smokers contained solely two AhR/Wnt-variants. The optimal decision tree for never smokers consists of 7 AhR/Wnt-variants and only two lung cancer variants., Conclusions: The role of variants belonging to Wnt/AhR-pathways in lung cancer susceptibility may be underrated in main-effects association analysis. Complex interaction patterns in individuals of European descent have moderate predictive capacity for lung cancer or subgroups thereof, especially in never smokers., (© 2022. The Author(s).)- Published
- 2022
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22. Oncolytic herpesvirus therapy for mesothelioma - A phase I/IIa trial of intrapleural administration of HSV1716.
- Author
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Danson SJ, Conner J, Edwards JG, Blyth KG, Fisher PM, Muthana M, Salawu A, Taylor F, Hodgkinson E, Joyce P, Roman J, Simpson K, Graham A, Learmonth K, and Woll PJ
- Subjects
- Humans, Pleura, Simplexvirus, Lung Neoplasms therapy, Mesothelioma therapy, Pleural Neoplasms therapy
- Abstract
Objectives: Malignant Pleural Mesothelioma (MPM) remains a major oncological challenge with limited therapeutic options. HSV1716 is a replication restricted oncolytic herpes simplex virus with anti-tumor effects in multiple cell lines including MPM. Intrapleural treatment appeals because MPM is typically multifocal but confined to the pleura, and distant metastases are uncommon. We assessed the safety and possible efficacy of intrapleural HSV1716 for inoperable MPM., Materials and Methods: Patients with MPM received 1 × 10
7 iu HSV1716 injected via an indwelling intrapleural catheter (IPC) on one, two or four occasions a week apart. The primary endpoint was the safety and tolerability of HSV1716. Secondary endpoints were assessment of HSV1716 replication, detection of immune response and evaluation of tumor response., Results: Of thirteen patients enrolled, five had received previous pemetrexed-cisplatin chemotherapy, and eight were chemotherapy naïve. Three patients were enrolled to receive one dose, three patients to two doses and seven patients to four doses. The treatment was well-tolerated with few virus-related adverse events and no dose limiting toxicities. Twelve patients were evaluable for response, as one patient withdrew early after a catheter fracture. There was evidence of viral replication/persistence in pleural fluid in seven of the twelve patients. Induction of Th1 cytokine responses to HSV1716 treatment occurred in eight patients and four patients developed novel anti-tumor IgG. No objective responses were observed but disease stabilization was reported in 50 % of patients at 8 weeks., Conclusions: Intrapleural HSV1716 was well-tolerated and demonstrated an anti-tumor immune response in MPM patients. These results provide a rationale for further studies with this agent in MPM and in combination with other therapies., (Copyright © 2020 Elsevier B.V. All rights reserved.)- Published
- 2020
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23. Ganetespib in Combination with Pemetrexed-Platinum Chemotherapy in Patients with Pleural Mesothelioma (MESO-02): A Phase Ib Trial.
- Author
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Fennell DA, Danson S, Woll PJ, Forster M, Talbot D, Child J, Farrelly L, Sharkey A, Busacca S, Ngai Y, Hackshaw A, and Wheeler GM
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- Adult, Aged, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Carboplatin administration & dosage, Carboplatin adverse effects, Cisplatin administration & dosage, Cisplatin adverse effects, Female, Humans, Infusions, Intravenous, Injection Site Reaction etiology, Male, Mesothelioma, Malignant mortality, Mesothelioma, Malignant pathology, Middle Aged, Nausea chemically induced, Pemetrexed administration & dosage, Pemetrexed adverse effects, Progression-Free Survival, Triazoles administration & dosage, Antineoplastic Combined Chemotherapy Protocols adverse effects, Injection Site Reaction epidemiology, Mesothelioma, Malignant drug therapy, Nausea epidemiology, Triazoles adverse effects
- Abstract
Purpose: Ganetespib, a highly potent, small-molecule Heatshock protein 90 inhibitor, has potential efficacy in malignant pleural mesothelioma (MPM) via activity on critical survival pathways and known synergies with antifolates and platinum chemotherapy. We conducted a dose-escalation study to identify the maximum tolerated dose (MTD) of ganetespib in patients with chemotherapy-naïve MPM., Patients and Methods: MESO-02 (ClinicalTrials.gov: NCT01590160) was a nonrandomized, multicenter, phase Ib trial of 3-weekly ganetespib (100 mg/m
2 , 150 mg/m2 , 200 mg/m2 ; days 1 and 15) with pemetrexed (500 mg/m2 ; day 1) and cisplatin (75 mg/m2 ; day 1) or carboplatin (area under concentration-time curve 5; day 1) in patients with MPM. Dose escalation was performed using the 3 + 3 design (cisplatin) and accelerated titration design (carboplatin). Secondary endpoints included best response, progression-free survival (PFS), and pharmacogenomic analyses., Results: Of 27 patients enrolled (cisplatin, n = 16; carboplatin, n = 11), 3 experienced dose-limiting toxicities: grade 3 nausea (cisplatin, n = 1; carboplatin, n = 1) and grade 2 infusion-related reaction (carboplatin, n = 1). Ganetespib's MTD was 200 mg/m2 . Partial response was observed in 14 of 27 patients (52%; 61% in 23 response-evaluable patients) and 13 of 21 (62%) with epithelioid histology. At the MTD, 10 of 18 patients (56%) had partial response, 15 of 18 (83%) had disease control, and median PFS was 6.3 months (95% CI, 5.0-10.0). One responder exhibited disease control beyond 50 months. Global loss of heterozygosity was associated with shorter time to progression (HR 1.12; 95% CI, 1.02-1.24; P = 0.018)., Conclusions: Ganetespib can be combined safely with pemetrexed and platinum chemotherapy to treat patients with MPM. This class of agent should be investigated in larger randomized studies., (©2020 American Association for Cancer Research.)- Published
- 2020
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24. Association Analysis of Driver Gene-Related Genetic Variants Identified Novel Lung Cancer Susceptibility Loci with 20,871 Lung Cancer Cases and 15,971 Controls.
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Wang Y, Gorlova OY, Gorlov IP, Zhu M, Dai J, Albanes D, Lam S, Tardon A, Chen C, Goodman GE, Bojesen SE, Landi MT, Johansson M, Risch A, Wichmann HE, Bickeboller H, Christiani DC, Rennert G, Arnold SM, Brennan P, Field JK, Shete S, Le Marchand L, Melander O, Brunnstrom H, Liu G, Hung RJ, Andrew AS, Kiemeney LA, Zienolddiny S, Grankvist K, Johansson M, Caporaso NE, Woll PJ, Lazarus P, Schabath MB, Aldrich MC, Stevens VL, Ma H, Jin G, Hu Z, Amos CI, and Shen H
- Subjects
- Case-Control Studies, Female, Humans, Male, Middle Aged, Genetic Predisposition to Disease genetics, Genetic Variation genetics, Genome-Wide Association Study methods, Lung Neoplasms genetics
- Abstract
Background: A substantial proportion of cancer driver genes (CDG) are also cancer predisposition genes. However, the associations between genetic variants in lung CDGs and the susceptibility to lung cancer have rarely been investigated., Methods: We selected expression-related single-nucleotide polymorphisms (eSNP) and nonsynonymous variants of lung CDGs, and tested their associations with lung cancer risk in two large-scale genome-wide association studies (20,871 cases and 15,971 controls of European descent). Conditional and joint association analysis was performed to identify independent risk variants. The associations of independent risk variants with somatic alterations in lung CDGs or recurrently altered pathways were investigated using data from The Cancer Genome Atlas (TCGA) project., Results: We identified seven independent SNPs in five lung CDGs that were consistently associated with lung cancer risk in discovery ( P < 0.001) and validation ( P < 0.05) stages. Among these loci, rs78062588 in TPM3 (1q21.3) was a new lung cancer susceptibility locus (OR = 0.86, P = 1.65 × 10
-6 ). Subgroup analysis by histologic types further identified nine lung CDGs. Analysis of somatic alterations found that in lung adenocarcinomas, rs78062588[C] allele ( TPM3 in 1q21.3) was associated with elevated somatic copy number of TPM3 (OR = 1.16, P = 0.02). In lung adenocarcinomas, rs1611182 ( HLA-A in 6p22.1) was associated with truncation mutations of the transcriptional misregulation in cancer pathway (OR = 0.66, P = 1.76 × 10-3 )., Conclusions: Genetic variants can regulate functions of lung CDGs and influence lung cancer susceptibility., Impact: Our findings might help unravel biological mechanisms underlying lung cancer susceptibility., (©2020 American Association for Cancer Research.)- Published
- 2020
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25. The clinical role of VeriStrat testing in patients with advanced non-small cell lung cancer considered unfit for first-line platinum-based chemotherapy.
- Author
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Lee SM, Upadhyay S, Lewanski C, Falk S, Skailes G, Woll PJ, Hatton M, Lal R, Jones R, Toy E, Rudd R, Ngai Y, Edwards A, and Hackshaw A
- Subjects
- Adenocarcinoma of Lung drug therapy, Adenocarcinoma of Lung pathology, Aged, Aged, 80 and over, Blood Proteins analysis, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung pathology, Carcinoma, Squamous Cell drug therapy, Carcinoma, Squamous Cell pathology, Double-Blind Method, Female, Follow-Up Studies, Humans, Lung Neoplasms drug therapy, Lung Neoplasms pathology, Male, Middle Aged, Predictive Value of Tests, Protein Kinase Inhibitors therapeutic use, Proteomics, Survival Rate, Adenocarcinoma of Lung blood, Biomarkers, Tumor blood, Carcinoma, Non-Small-Cell Lung blood, Carcinoma, Squamous Cell blood, Erlotinib Hydrochloride therapeutic use, Lung Neoplasms blood, Platinum therapeutic use
- Abstract
Purpose: We previously demonstrated that the median survival of patients with poor prognosis non-small cell lung cancer (NSCLC) considered unfit for first-line platinum chemotherapy was <4 months. We evaluated whether VeriStrat could be used as a prognostic or predictive biomarker in this population., Experimental Design: We conducted a randomised double-blind trial among patients with untreated advanced NSCLC considered unfit for platinum chemotherapy because of poor performance status (PS) or multiple comorbidities. All patients received active supportive care (ASC) and were treated with either oral erlotinib or placebo daily. Five hundred twenty-seven patients had plasma samples for VeriStrat classification: good (VeriStrat Good [VSG]) or poor (VeriStrat Poor [VSP]). Main end-point was overall survival., Results: Fifty-five percent patients had VSG, and 83% had Eastern Cooperative Oncology Group (ECOG) 2-3 at baseline. VeriStrat was strongly associated with survival. Among patients managed with ASC only, the adjusted hazard ratio (HR) was 0.54 (p < 0.001) for VSG versus VSP. The association was consistent across patient factors: HR = 0.25 (p = 0.004) and HR = 0.56 (p < 0.001) for ECOG 0-1 and 2-3, respectively, HR = 0.49 (0070 < 0.001) for age≥75 years and HR = 0.59 (p = 0.007) for stage IV. Several ECOG 2-3 patients had long survival: 2-year survival was 8% for VSG patients who had ASC, compared with 0% for VSP. VeriStrat status did not predict benefit from erlotinib treatment because the HRs for erlotinib versus placebo were similar between VSG and VSP patients., Conclusions: VeriStrat was not a predictive marker for survival when considering first-line erlotinib for patients with NSCLC who had poor PS and were not recommended for platinum doublet therapies. However, VeriStrat was an independent prognostic marker of survival. It represents an objective measurement that could be considered alongside other patient factors to provide a more refined assessment of prognosis for this particular patient group. VSG patients could be selected for treatment trials because of better survival, while VSP patients can continue to be treated conservatively or offered trials of less toxic agents., Trial Registration Isrctn Number: ISRCTN02370070., (Crown Copyright © 2019. Published by Elsevier Ltd. All rights reserved.)
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- 2019
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26. Elevated Platelet Count Appears to Be Causally Associated with Increased Risk of Lung Cancer: A Mendelian Randomization Analysis.
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Zhu Y, Wei Y, Zhang R, Dong X, Shen S, Zhao Y, Bai J, Albanes D, Caporaso NE, Landi MT, Zhu B, Chanock SJ, Gu F, Lam S, Tsao MS, Shepherd FA, Tardon A, Fernández-Somoano A, Fernandez-Tardon G, Chen C, Barnett MJ, Doherty J, Bojesen SE, Johansson M, Brennan P, McKay JD, Carreras-Torres R, Muley T, Risch A, Wichmann HE, Bickeboeller H, Rosenberger A, Rennert G, Saliba W, Arnold SM, Field JK, Davies MPA, Marcus MW, Wu X, Ye Y, Le Marchand L, Wilkens LR, Melander O, Manjer J, Brunnström H, Hung RJ, Liu G, Brhane Y, Kachuri L, Andrew AS, Duell EJ, Kiemeney LA, van der Heijden EH, Haugen A, Zienolddiny S, Skaug V, Grankvist K, Johansson M, Woll PJ, Cox A, Taylor F, Teare DM, Lazarus P, Schabath MB, Aldrich MC, Houlston RS, McLaughlin J, Stevens VL, Shen H, Hu Z, Dai J, Amos CI, Han Y, Zhu D, Goodman GE, Chen F, and Christiani DC
- Subjects
- Adenocarcinoma of Lung genetics, Adenocarcinoma of Lung pathology, Biomarkers, Tumor blood, Biomarkers, Tumor genetics, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung pathology, Carcinoma, Squamous Cell genetics, Carcinoma, Squamous Cell pathology, Case-Control Studies, Genetic Predisposition to Disease, Humans, Lung Neoplasms genetics, Lung Neoplasms pathology, Mendelian Randomization Analysis, Platelet Count, Polymorphism, Single Nucleotide, Prognosis, Risk Factors, Small Cell Lung Carcinoma genetics, Small Cell Lung Carcinoma pathology, Adenocarcinoma of Lung blood, Blood Platelets pathology, Carcinoma, Non-Small-Cell Lung blood, Carcinoma, Squamous Cell blood, Lung Neoplasms blood, Small Cell Lung Carcinoma blood
- Abstract
Background: Platelets are a critical element in coagulation and inflammation, and activated platelets are linked to cancer risk through diverse mechanisms. However, a causal relationship between platelets and risk of lung cancer remains unclear., Methods: We performed single and combined multiple instrumental variable Mendelian randomization analysis by an inverse-weighted method, in addition to a series of sensitivity analyses. Summary data for associations between SNPs and platelet count are from a recent publication that included 48,666 Caucasian Europeans, and the International Lung Cancer Consortium and Transdisciplinary Research in Cancer of the Lung data consisting of 29,266 cases and 56,450 controls to analyze associations between candidate SNPs and lung cancer risk., Results: Multiple instrumental variable analysis incorporating six SNPs showed a 62% increased risk of overall non-small cell lung cancer [NSCLC; OR, 1.62; 95% confidence interval (CI), 1.15-2.27; P = 0.005] and a 200% increased risk for small-cell lung cancer (OR, 3.00; 95% CI, 1.27-7.06; P = 0.01). Results showed only a trending association with NSCLC histologic subtypes, which may be due to insufficient sample size and/or weak effect size. A series of sensitivity analysis retained these findings., Conclusions: Our findings suggest a causal relationship between elevated platelet count and increased risk of lung cancer and provide evidence of possible antiplatelet interventions for lung cancer prevention., Impact: These findings provide a better understanding of lung cancer etiology and potential evidence for antiplatelet interventions for lung cancer prevention., (©2019 American Association for Cancer Research.)
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- 2019
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27. The impact of chemotherapy on survival of patients with extremity and trunk wall soft tissue sarcoma: revisiting the results of the EORTC-STBSG 62931 randomised trial.
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Pasquali S, Pizzamiglio S, Touati N, Litiere S, Marreaud S, Kasper B, Gelderblom H, Stacchiotti S, Judson I, Dei Tos AP, Verderio P, Casali PG, Woll PJ, and Gronchi A
- Subjects
- Adolescent, Adult, Aged, Doxorubicin administration & dosage, Female, Follow-Up Studies, Humans, Ifosfamide administration & dosage, Male, Middle Aged, Prognosis, Sarcoma drug therapy, Sarcoma pathology, Survival Rate, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Chemotherapy, Adjuvant mortality, Extremities pathology, Neoadjuvant Therapy mortality, Nomograms, Sarcoma mortality, Torso pathology
- Abstract
Background: This study was aimed at determining whether patients with high-risk soft tissue sarcoma (STS), as identified using the nomogram Sarculator, benefitted from adjuvant chemotherapy in the EORTC-STBSG 62931 randomised controlled trial (RCT), which failed to detect an impact for adjuvant doxorubicin plus ifosfamide (Adj) over observation (Obs)., Methods: Patients with extremity and trunk wall STS in the EORTC-STBSG 62931 RCT were analysed (N = 290/351). Ten-year predicted probability of overall survival (pr-OS) was calculated using the prognostic nomogram Sarculator. Patients were grouped into three categories of predicted pr-OS: high (pr-OS>66%), intermediate (51
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- 2019
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28. Gemcitabine and docetaxel versus doxorubicin as first-line treatment in previously untreated advanced unresectable or metastatic soft-tissue sarcomas (GeDDiS): a randomised controlled phase 3 trial.
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Seddon B, Strauss SJ, Whelan J, Leahy M, Woll PJ, Cowie F, Rothermundt C, Wood Z, Benson C, Ali N, Marples M, Veal GJ, Jamieson D, Küver K, Tirabosco R, Forsyth S, Nash S, Dehbi HM, and Beare S
- Subjects
- Adult, Antineoplastic Combined Chemotherapy Protocols adverse effects, Confidence Intervals, Deoxycytidine administration & dosage, Deoxycytidine adverse effects, Deoxycytidine analogs & derivatives, Disease-Free Survival, Docetaxel, Dose-Response Relationship, Drug, Doxorubicin administration & dosage, Doxorubicin adverse effects, Drug Administration Schedule, Female, Humans, Infusions, Intravenous, Kaplan-Meier Estimate, Male, Middle Aged, Neoplasm Invasiveness pathology, Neoplasm Metastasis, Neoplasm Staging, Prognosis, Sarcoma mortality, Soft Tissue Neoplasms mortality, Survival Analysis, Taxoids administration & dosage, Taxoids adverse effects, Treatment Outcome, United Kingdom, Gemcitabine, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Sarcoma drug therapy, Sarcoma pathology, Soft Tissue Neoplasms drug therapy, Soft Tissue Neoplasms pathology
- Abstract
Background: For many years, first-line treatment for locally advanced or metastatic soft-tissue sarcoma has been doxorubicin. This study compared gemcitabine and docetaxel versus doxorubicin as first-line treatment for advanced or metastatic soft-tissue sarcoma., Methods: The GeDDiS trial was a randomised controlled phase 3 trial done in 24 UK hospitals and one Swiss Group for Clinical Cancer Research (SAKK) hospital. Eligible patients had histologically confirmed locally advanced or metastatic soft-tissue sarcoma of Trojani grade 2 or 3, disease progression before enrolment, and no previous chemotherapy for sarcoma or previous doxorubicin for any cancer. Patients were randomly assigned 1:1 to receive six cycles of intravenous doxorubicin 75 mg/m
2 on day 1 every 3 weeks, or intravenous gemcitabine 675 mg/m2 on days 1 and 8 and intravenous docetaxel 75 mg/m2 on day 8 every 3 weeks. Treatment was assigned using a minimisation algorithm incorporating a random element. Randomisation was stratified by age (≤18 years vs >18 years) and histological subtype. The primary endpoint was the proportion of patients alive and progression free at 24 weeks in the intention-to-treat population. Adherence to treatment and toxicity were analysed in the safety population, consisting of all patients who received at least one dose of their randomised treatment. The trial was registered with the European Clinical Trials (EudraCT) database (no 2009-014907-29) and with the International Standard Randomised Controlled Trial registry (ISRCTN07742377), and is now closed to patient entry., Findings: Between Dec 3, 2010, and Jan 20, 2014, 257 patients were enrolled and randomly assigned to the two treatment groups (129 to doxorubicin and 128 to gemcitabine and docetaxel). Median follow-up was 22 months (IQR 15·7-29·3). The proportion of patients alive and progression free at 24 weeks did not differ between those who received doxorubicin versus those who received gemcitabine and docetaxel (46·3% [95% CI 37·5-54·6] vs 46·4% [37·5-54·8]); median progression-free survival (23·3 weeks [95% CI 19·6-30·4] vs 23·7 weeks [18·1-20·0]; hazard ratio [HR] for progression-free survival 1·28, 95% CI 0·99-1·65, p=0·06). The most common grade 3 and 4 adverse events were neutropenia (32 [25%] of 128 patients who received doxorubicin and 25 [20%] of 126 patients who received gemcitabine and docetaxel), febrile neutropenia (26 [20%] and 15 [12%]), fatigue (eight [6%] and 17 [14%]), oral mucositis (18 [14%] and two [2%]), and pain (ten [8%] and 13 [10%]). The three most common serious adverse events, representing 111 (39%) of all 285 serious adverse events recorded, were febrile neutropenia (27 [17%] of 155 serious adverse events in patients who received doxorubicin and 15 [12%] of 130 serious adverse events in patients who received gemcitabine and docetaxel, fever (18 [12%] and 19 [15%]), and neutropenia (22 [14%] and ten [8%]). 154 (60%) of 257 patients died in the intention-to-treat population: 74 (57%) of 129 patients in the doxorubicin group and 80 (63%) of 128 in the gemcitabine and docetaxel group. No deaths were related to the treatment, but two deaths were due to a combination of disease progression and treatment., Interpretation: Doxorubicin should remain the standard first-line treatment for most patients with advanced soft-tissue sarcoma. These results provide evidence for clinicians to consider with their patients when selecting first-line treatment for locally advanced or metastatic soft-tissue sarcoma., Funding: Cancer Research UK, Sarcoma UK, and Clinical Trial Unit Kantonsspital St Gallen., (Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)- Published
- 2017
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29. Carboplatin versus two doses of cisplatin in combination with gemcitabine in the treatment of advanced non-small-cell lung cancer: Results from a British Thoracic Oncology Group randomised phase III trial.
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Ferry D, Billingham L, Jarrett H, Dunlop D, Woll PJ, Nicolson M, Shah R, Thompson J, Spicer J, Muthukumar D, Skailes G, Leonard P, Chetiyawardana AD, Wells P, Lewanski C, Crosse B, Hill M, Gaunt P, and O'Byrne K
- Subjects
- Adult, Aged, Aged, 80 and over, Carboplatin administration & dosage, Carcinoma, Non-Small-Cell Lung pathology, Cisplatin administration & dosage, Deoxycytidine administration & dosage, Deoxycytidine analogs & derivatives, Female, Humans, Lung Neoplasms pathology, Male, Middle Aged, Proportional Hazards Models, Quality of Life, Survival Analysis, Gemcitabine, Antineoplastic Agents therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Neoplasms drug therapy
- Abstract
Background: Platinum-based combination chemotherapy is standard treatment for the majority of patients with advanced non-small-cell lung cancer (NSCLC). The trial investigates the importance of the choice of platinum agent and dose of cisplatin in relation to patient outcomes., Methods: The three-arm randomised phase III trial assigned patients with chemo-naïve stage IIIB/IV NSCLC in a 1:1:1 ratio to receive gemcitabine 1250 mg/m
2 on days 1 and 8 of a 3-week cycle with cisplatin 80 mg/m2 (GC80) or cisplatin 50 mg/m2 (GC50) or carboplatin AUC6 (GCb6) for a maximum of four cycles. Primary outcome measure was survival time, aiming to test for a difference between treatment arms and also assess non-inferiority with pre-defined margin selected as hazard ratio (HR) of 1.2. Secondary outcome measures included response rate, adverse events and quality of life (QoL)., Findings: The trial recruited 1363 patients. Survival time differed significantly across the three treatment arms (p = 0.046) with GC50 worst with median 8.2 months compared to 9.5 for GC80 and 10.0 for GCb6. HRs (adjusted) for GC50 compared to GC80 was 1.13 (95% confidence interval [CI] 0.99-1.29) and for GC50 compared to GCb6 was 1.23 (95% CI: 1.08-1.41). GCb6 was significantly non-inferior to GC80 (HR = 0.93, upper limit of one-sided 95% CI 1.04). Adjusting for QoL did not change the findings. Best objective response rates were 29% (GC80), 20% (GC50) and 27% (GCb6), p < 0.007. There were more dose reductions and treatment delays in the GCb6 arm and more adverse events (60% with at least one grade 3-4 compared to 43% GC80 and 30% GC50)., Interpretation: In combination with gemcitabine, carboplatin at AUC6 is not inferior to cisplatin at 80 mg/m2 in terms of survival. Carboplatin was associated with more adverse events and not with better quality of life. Cisplatin at the lower dose of 50 mg/m2 has worse survival which is not compensated by better quality of life. CLINICALTRIALS., Gov Identifier: NCT00112710., Eudract Number: 2004-003868-30., Cancer Research Uk Trial Identifier: CRUK/04/009., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)- Published
- 2017
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30. Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): an open-label, phase 3, randomised, superiority trial.
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Faivre-Finn C, Snee M, Ashcroft L, Appel W, Barlesi F, Bhatnagar A, Bezjak A, Cardenal F, Fournel P, Harden S, Le Pechoux C, McMenemin R, Mohammed N, O'Brien M, Pantarotto J, Surmont V, Van Meerbeeck JP, Woll PJ, Lorigan P, and Blackhall F
- Subjects
- Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols adverse effects, Chemoradiotherapy adverse effects, Chemoradiotherapy methods, Cisplatin administration & dosage, Dose Fractionation, Radiation, Esophagitis etiology, Etoposide administration & dosage, Female, Follow-Up Studies, Humans, Intention to Treat Analysis, Lung Neoplasms pathology, Male, Middle Aged, Neoplasm Staging, Neutropenia etiology, Radiation Pneumonitis etiology, Small Cell Lung Carcinoma pathology, Survival Rate, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Lung Neoplasms therapy, Small Cell Lung Carcinoma therapy
- Abstract
Background: Concurrent chemoradiotherapy is the standard of care in limited-stage small-cell lung cancer, but the optimal radiotherapy schedule and dose remains controversial. The aim of this study was to establish a standard chemoradiotherapy treatment regimen in limited-stage small-cell lung cancer., Methods: The CONVERT trial was an open-label, phase 3, randomised superiority trial. We enrolled adult patients (aged ≥18 years) who had cytologically or histologically confirmed limited-stage small-cell lung cancer, Eastern Cooperative Oncology Group performance status of 0-2, and adequate pulmonary function. Patients were recruited from 73 centres in eight countries. Patients were randomly assigned to receive either 45 Gy radiotherapy in 30 twice-daily fractions of 1·5 Gy over 19 days, or 66 Gy in 33 once-daily fractions of 2 Gy over 45 days, starting on day 22 after commencing cisplatin-etoposide chemotherapy (given as four to six cycles every 3 weeks in both groups). The allocation method used was minimisation with a random element, stratified by institution, planned number of chemotherapy cycles, and performance status. Treatment group assignments were not masked. The primary endpoint was overall survival, defined as time from randomisation until death from any cause, analysed by modified intention-to-treat. A 12% higher overall survival at 2 years in the once-daily group versus the twice-daily group was considered to be clinically significant to show superiority of the once-daily regimen. The study is registered with ClinicalTrials.gov (NCT00433563) and is currently in follow-up., Findings: Between April 7, 2008, and Nov 29, 2013, 547 patients were enrolled and randomly assigned to receive twice-daily concurrent chemoradiotherapy (274 patients) or once-daily concurrent chemoradiotherapy (273 patients). Four patients (one in the twice-daily group and three in the once-daily group) did not return their case report forms and were lost to follow-up; these patients were not included in our analyses. At a median follow-up of 45 months (IQR 35-58), median overall survival was 30 months (95% CI 24-34) in the twice-daily group versus 25 months (21-31) in the once-daily group (hazard ratio for death in the once daily group 1·18 [95% CI 0·95-1·45]; p=0·14). 2-year overall survival was 56% (95% CI 50-62) in the twice-daily group and 51% (45-57) in the once-daily group (absolute difference between the treatment groups 5·3% [95% CI -3·2% to 13·7%]). The most common grade 3-4 adverse event in patients evaluated for chemotherapy toxicity was neutropenia (197 [74%] of 266 patients in the twice-daily group vs 170 [65%] of 263 in the once-daily group). Most toxicities were similar between the groups, except there was significantly more grade 4 neutropenia with twice-daily radiotherapy (129 [49%] vs 101 [38%]; p=0·05). In patients assessed for radiotherapy toxicity, was no difference in grade 3-4 oesophagitis between the groups (47 [19%] of 254 patients in the twice-daily group vs 47 [19%] of 246 in the once-daily group; p=0·85) and grade 3-4 radiation pneumonitis (4 [3%] of 254 vs 4 [2%] of 246; p=0·70). 11 patients died from treatment-related causes (three in the twice-daily group and eight in the once-daily group)., Interpretation: Survival outcomes did not differ between twice-daily and once-daily concurrent chemoradiotherapy in patients with limited-stage small-cell lung cancer, and toxicity was similar and lower than expected with both regimens. Since the trial was designed to show superiority of once-daily radiotherapy and was not powered to show equivalence, the implication is that twice-daily radiotherapy should continue to be considered the standard of care in this setting., Funding: Cancer Research UK (Clinical Trials Awards and Advisory Committee), French Ministry of Health, Canadian Cancer Society Research Institute, European Organisation for Research and Treatment of Cancer (Cancer Research Fund, Lung Cancer, and Radiation Oncology Groups)., (Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC-BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)
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- 2017
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31. The use of bisphosphonates in the management of bone involvement from solid tumours and haematological malignancies - a European survey.
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Lebret T, Casas A, Cavo M, Woll PJ, Deleplace C, Kennedy C, Schoen P, and Jackisch C
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- Aged, Bone Neoplasms secondary, Europe, Female, Hematologic Neoplasms, Humans, Male, Middle Aged, Patient Safety, Time-to-Treatment, Treatment Outcome, Bone Density Conservation Agents therapeutic use, Bone Neoplasms drug therapy, Diphosphonates therapeutic use, Neoplasms
- Abstract
Bone metastases in patients with solid tumours (ST) and bone lesions in patients with haematological malignancies (HM) are common. Associated skeletal-related events (SREs) cause severe pain, reduced quality of life and place a burden on health care resources. Bone-targeted agents can reduce the risk of SREs. We evaluated the management of bone metastasis/lesions in five European countries (France, Germany, Italy, Spain and the UK) by an observational chart audit. In total, 881 physicians completed brief questionnaires on 17 193 patients during the observation period, and detailed questionnaires for a further 9303 individuals. Patient cases were weighted according to the probability of inclusion. Although a large proportion of patients with bone metastases/lesions were receiving bisphosphonates, many had their treatment stopped (ST, 19%; HM, 36%) or will never be treated (ST, 18%; HM, 13%). The results were generally similar across the countries, although German patients were more likely to have asymptomatic bone lesions detected during routine imaging. In conclusion, many patients who could benefit from bone-targeted agents do not receive bisphosphonates and many have their treatment stopped when they could benefit from continued treatment. Developing treatment guidelines, educating physicians and increasing the availability of new agents could benefit patients and reduce costs., (© 2016 The Authors. European Journal of Cancer Care Published by John Wiley & Sons Ltd.)
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- 2017
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32. Anti-angiogenic therapies for the treatment of angiosarcoma: a clinical update.
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Young RJ and Woll PJ
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Angiosarcomas are rare aggressive endothelial tumours, and are associated with a poor prognosis. Due to their vascular nature, there is great interest in their response to anti-angiogenic agents. A number of small prospective studies have reported angiosarcoma response to vascular-targeted agents, including agents that target vascular endothelial growth factor. To date, the response to these agents has been disappointing, and similar to the response observed in other soft tissue sarcoma subtypes. This short review will summarise the recent data in this field., Competing Interests: R.J. Young and P.J. Woll declare that they have no competing interests.
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- 2017
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33. Outcome and Biomarker Analysis from a Multicenter Phase 2 Study of Ipilimumab in Combination with Carboplatin and Etoposide as First-Line Therapy for Extensive-Stage SCLC.
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Arriola E, Wheater M, Galea I, Cross N, Maishman T, Hamid D, Stanton L, Cave J, Geldart T, Mulatero C, Potter V, Danson S, Woll PJ, Griffiths R, Nolan L, and Ottensmeier C
- Subjects
- Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal administration & dosage, Antineoplastic Combined Chemotherapy Protocols adverse effects, Autoantibodies blood, Carboplatin administration & dosage, Etoposide administration & dosage, Female, Humans, Ipilimumab, Lung Neoplasms mortality, Lung Neoplasms pathology, Male, Middle Aged, Neoplasm Staging, Small Cell Lung Carcinoma mortality, Small Cell Lung Carcinoma pathology, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Biomarkers, Tumor analysis, Lung Neoplasms drug therapy, Small Cell Lung Carcinoma drug therapy
- Abstract
Objectives: Our aim was to evaluate the safety and efficacy of ipilimumab combined with standard first-line chemotherapy for patients with extensive-stage SCLC., Methods: Patients with chemotherapy-naive extensive-stage SCLC were treated with carboplatin and etoposide for up to six cycles. Ipilimumab, 10 mg/kg, was given on day 1 of cycles 3 to 6 and every 12 weeks. Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.0, and immune-related response criteria. The primary end point was 1-year progression-free survival (PFS) according to RECIST. Secondary end points included PFS according to immune-related PFS and overall survival. Autoantibody serum levels were evaluated and correlated with clinical outcomes., Results: A total of 42 patients were enrolled between September 2011 and April 2014; 39 were evaluable for safety and 38 for efficacy. Six of 38 patients (15.8% [95% confidence interval (CI): 7.4-30.4]) were alive and progression-free at 1-year by RECIST. Median PFS was 6.9 months (95% CI: 5.5-7.9). Median immune-related PFS was 7.3 months (95% CI: 5.5-8.8). Median overall survival was 17.0 months (95% CI: 7.9-24.3). Of the patients evaluable for response, 21 of 29 (72.4%) achieved an objective response by RECIST and 28 of 33 (84.8%) achieved an objective response by the immune-related response criteria. All patients experienced at least one adverse event; at least one grade 3 or higher toxicity developed in 35 of 39 patients (89.7%); in 27 patients (69.2%) this was related to ipilimumab. Five deaths were reported to be related to ipilimumab. Positivity of an autoimmune profile at baseline was associated with improved outcomes and severe neurological toxicity., Conclusions: Ipilimumab in combination with carboplatin and etoposide might benefit a subgroup of patients with advanced SCLC. Autoantibody analysis correlates with treatment benefit and toxicity and warrants further investigation., (Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)
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- 2016
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34. Phase I study of IMGN901, a CD56-targeting antibody-drug conjugate, in patients with CD56-positive solid tumors.
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Shah MH, Lorigan P, O'Brien ME, Fossella FV, Moore KN, Bhatia S, Kirby M, and Woll PJ
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- Administration, Intravenous, Adolescent, Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal adverse effects, Antibodies, Monoclonal therapeutic use, Antineoplastic Agents, Immunological therapeutic use, Dose-Response Relationship, Drug, Female, Humans, Male, Maximum Tolerated Dose, Maytansine administration & dosage, Maytansine adverse effects, Maytansine therapeutic use, Middle Aged, Neoplasms pathology, Treatment Outcome, Young Adult, Antibodies, Monoclonal administration & dosage, Antineoplastic Agents, Immunological administration & dosage, Antineoplastic Agents, Immunological adverse effects, CD56 Antigen immunology, Maytansine analogs & derivatives, Neoplasms drug therapy
- Abstract
Background IMGN901 is a CD56-targeting antibody-drug conjugate designed for tumor-selective delivery of the cytotoxic maytansinoid DM1. This phase 1 study investigated the safety, tolerability, pharmacokinetics, and preliminary activity of IMGN901 in patients with CD56-expressing solid tumors. Methods Patients were enrolled in cohorts of escalating IMGN901 doses, administered intravenously, on 3 consecutive days every 21 days. A dose-expansion phase accrued patients with small cell lung cancer (SCLC), Merkel cell carcinoma (MCC), or ovarian cancer. Results Fifty-two patients were treated at doses escalating from 4 to 94 mg/m(2)/day. The maximum tolerated dose (MTD) was determined to be 75 mg/m(2). Dose-limiting toxicities included fatigue, neuropathy, headache or meningitis-like symptoms, chest pain, dyspnea, and myalgias. In the dose-expansion phase (n = 45), seven patients received 75 mg/m(2) and 38 received 60 mg/m(2) for up to 21 cycles. The recommended phase 2 dose (RP2D) was established at 60 mg/m(2) during dose expansion. Overall, treatment-emergent adverse events (TEAEs) were experienced by 96.9 % of all patients, the majority of which were Grade 1 or 2. The most commonly reported Grade 3 or 4 TEAEs were hyponatremia and dyspnea (each 8.2 %). Responses included 1 complete response (CR), 1 clinical CR, and 1 unconfirmed partial response (PR) in MCC; and 1 unconfirmed PR in SCLC. Stable disease was seen for 25 % of all evaluable patients who received doses ≥60 mg/m(2). Conclusions The RP2D for IMGN901 of 60 mg/m(2) administered for 3 consecutive days every 3 weeks was associated with an acceptable tolerability profile. Objective responses were observed in patients with advanced CD56+ cancers.
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- 2016
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35. Eribulin in soft-tissue sarcoma.
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Young RJ and Woll PJ
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- Female, Humans, Male, Antineoplastic Agents therapeutic use, Dacarbazine therapeutic use, Furans therapeutic use, Ketones therapeutic use, Leiomyosarcoma drug therapy, Liposarcoma drug therapy, Soft Tissue Neoplasms drug therapy
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- 2016
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36. The relationship between smoking and quality of life in advanced lung cancer patients: a prospective longitudinal study.
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Danson SJ, Rowland C, Rowe R, Ellis S, Crabtree C, Horsman JM, Wadsley J, Hatton MQ, Woll PJ, and Eiser C
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- Aged, Aged, 80 and over, Female, Humans, Longitudinal Studies, Male, Middle Aged, Prospective Studies, Surveys and Questionnaires, Lung Neoplasms psychology, Quality of Life psychology, Smoking psychology, Smoking Cessation methods
- Abstract
Purpose: Smoking is a major cause of lung cancer, and continued smoking may compromise treatment efficacy and quality of life (health-related quality of life (HRQoL)) in patients with advanced lung cancer. Our aims were to determine (i) preference for treatments which promote quality over length of life depending on smoking status, (ii) the relationship between HRQoL and smoking status at diagnosis (T1), after controlling for demographic and clinical variables, and (iii) changes in HRQoL 6 months after diagnosis (T2) depending on smoking status., Methods: Two hundred ninety-six patients with advanced lung cancer were given questionnaires to assess HRQoL (EORTC QLQ-C30), time-trade-off for life quality versus quantity (QQQ) and smoking history (current, former or never smoker) at diagnosis (T1) and 6 months later (T2). Medical data were extracted from case records., Results: Questionnaires were returned by 202 (68.2 %) patients at T1 and 114 (53.3 %) at T2. Patients favoured treatments that would enhance quality of life over increased longevity. Those who continued smoking after diagnosis reported worse HRQoL than former smokers or those who never smoked. Smoking status was a significant independent predictor of coughing in T1 (worse in smokers) and cognitive functioning in T2 (better in never smokers)., Conclusions: Smoking by patients with advanced lung cancer is associated with worse symptoms on diagnosis and poorer HRQoL for those who continue smoking. The results have implications to help staff explain the consequences of smoking to patients.
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- 2016
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37. Quality of life, support and smoking in advanced lung cancer patients: a qualitative study.
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Rowland C, Danson SJ, Rowe R, Merrick H, Woll PJ, Hatton MQ, Wadsley J, Ellis S, Crabtree C, Horsman JM, and Eiser C
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- Adaptation, Psychological, Aged, Female, Humans, Male, Middle Aged, Palliative Care, Qualitative Research, Smoking Cessation psychology, Lung Neoplasms psychology, Quality of Life psychology, Smoking adverse effects
- Abstract
Background: Lung cancer is the most common cancer and smoking is the principal cause. Due to poor survival rates, symptom palliation and promotion of health-related quality of life (HRQoL) are primary outcomes for lung cancer patients. Given the established relationship between smoking and lung cancer, patients who have smoked may feel stigmatised or guilty after diagnosis, and more pessimistic about their illness and likely outcomes. This may have adverse implications for HRQoL., Objectives: We explored HRQoL and support experiences among newly diagnosed patients with advanced lung cancer., Design: Semistructured interviews were conducted with nine patients and analysed using interpretative phenomenological analysis., Results: Patients described the physical, emotional and social impact of disease on HRQoL. Fear of compromising their immune system and adjusting to new relationship roles had a wide-ranging effect on patients' HRQoL. Patients acknowledged links between lung cancer and smoking but some continued to smoke. They were sensitive to the opinions of medical staff about smoking especially those who continued to smoke or recently quit., Conclusions: We conclude that staff should give clearer advice about the adverse implications of continued smoking. We discuss the potential value of diagnosis as a teachable moment for promoting smoking cessation among patients and family members., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)
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- 2016
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38. Randomized Phase III Trial of Standard Therapy Plus Low Molecular Weight Heparin in Patients With Lung Cancer: FRAGMATIC Trial.
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Macbeth F, Noble S, Evans J, Ahmed S, Cohen D, Hood K, Knoyle D, Linnane S, Longo M, Moore B, Woll PJ, Appel W, Dickson J, Ferry D, Brammer C, and Griffiths G
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- Aged, Anticoagulants therapeutic use, Drug Therapy, Combination, Female, Follow-Up Studies, Humans, Lung Neoplasms complications, Lung Neoplasms mortality, Male, Middle Aged, Neoplasm Staging, Prognosis, Standard of Care, Survival Rate, Venous Thromboembolism etiology, Venous Thromboembolism mortality, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Heparin, Low-Molecular-Weight therapeutic use, Lung Neoplasms drug therapy, Venous Thromboembolism prevention & control
- Abstract
Purpose: Venous thromboembolism (VTE) is common in cancer patients. Evidence has suggested that low molecular weight heparin (LMWH) might improve survival in patients with cancer by preventing both VTE and the progression of metastases. No trial in a single cancer type has been powered to demonstrate a clinically significant survival difference. The aim of this trial was to investigate this question in patients with lung cancer., Patients and Methods: We conducted a multicenter, open-label, randomized trial to evaluate the addition of a primary prophylactic dose of LMWH for 24 weeks to standard treatment in patients with newly diagnosed lung cancer of any stage and histology. The primary outcome was 1-year survival. Secondary outcomes included metastasis-free survival, VTE-free survival, toxicity, and quality of life., Results: For this trial, 2,202 patients were randomly assigned to the two treatment arms over 4 years. The trial did not reach its intended number of events for the primary analysis (2,047 deaths), and data were analyzed after 2,013 deaths after discussion with the independent data monitoring committee. There was no evidence of a difference in overall or metastasis-free survival between the two arms (hazard ratio [HR], 1.01; 95% CI, 0.93 to 1.10; P = .814; and HR, 0.99; 95% CI, 0.91 to 1.08; P = .864, respectively). There was a reduction in the risk of VTE from 9.7% to 5.5% (HR, 0.57; 95% CI, 0.42 to 0.79; P = .001) in the LMWH arm and no difference in major bleeding events but evidence of an increase in the composite of major and clinically relevant nonmajor bleeding in the LMWH arm., Conclusion: LMWH did not improve overall survival in the patients with lung cancer in this trial. A significant reduction in VTE is associated with an increase in clinically relevant nonmajor bleeding. Strategies to target those at greatest risk of VTE are warranted., (© 2015 by American Society of Clinical Oncology.)
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- 2016
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39. Unbiased Detection of Somatic Copy Number Aberrations in cfDNA of Lung Cancer Cases and High-Risk Controls with Low Coverage Whole Genome Sequencing.
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Taylor F, Bradford J, Woll PJ, Teare D, and Cox A
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- DNA, Neoplasm blood, Formaldehyde, Humans, Lung metabolism, Lung pathology, Lung Neoplasms blood, Lung Neoplasms diagnosis, Paraffin Embedding, Risk Factors, Sensitivity and Specificity, Tissue Fixation, DNA Copy Number Variations, DNA, Neoplasm genetics, Genome, Human genetics, High-Throughput Nucleotide Sequencing methods, Lung Neoplasms genetics
- Abstract
Molecular profiling using low coverage whole genome sequencing of cell free DNA (cfDNA) represents a non-targeted approach to identify multiple somatic copy number alterations (SCNA) across different lung cancer subtypes. We aim to establish that SCNA can be detected in cfDNA of lung cancer cases.Standard protocols were followed to process matched cfDNA, formalin-fixed paraffin embedded (FFPE) tumour and lymphocyte DNA. Copy number profiles for cfDNA or FFPE DNA were normalised to profiles from matched lymphocyte DNA with the software CNAnorm. Technical sensitivity was determined by spiking different proportions of FFPE tumour DNA into cfDNA from controls.The median genome coverage was 0.26X (range 0.05X-0.97X). For two advanced stage cases there was a positive correlation between copy number ratio profiles of matched cfDNA and FFPE DNA (r = 0.62, p < 0.0001 and r = 0.75, p < 0.0001). There was no correlation for four advanced and two early stage cases. There were low magnitude copy number aberrations detected in high-risk controls (N = 5). We detected spiked FFPE DNA derived SCNAs with a tumour fraction as low as 10 % of cfDNA.Our preliminary results demonstrate non-invasive detection of tumour-derived copy number alterations in advanced lung cancer cases with low coverage whole genome sequencing. Clinical characteristics and treatment may influence whether SCNA are detected in cfDNA.
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- 2016
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40. Maintenance pazopanib versus placebo in Non-Small Cell Lung Cancer patients non-progressive after first line chemotherapy: A double blind randomised phase III study of the lung cancer group, EORTC 08092 (EudraCT: 2010-018566-23, NCT01208064).
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O'Brien ME, Gaafar R, Hasan B, Menis J, Cufer T, Popat S, Woll PJ, Surmont V, Georgoulias V, Montes A, Blackhall F, Hennig I, Schmid-Bindert G, and Baas P
- Subjects
- Adult, Aged, Disease Progression, Disease-Free Survival, Double-Blind Method, Female, Humans, Indazoles, Kaplan-Meier Estimate, Male, Middle Aged, Protein Kinase Inhibitors adverse effects, Pyrimidines adverse effects, Sulfonamides adverse effects, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Neoplasms drug therapy, Maintenance Chemotherapy methods, Protein Kinase Inhibitors therapeutic use, Pyrimidines therapeutic use, Sulfonamides therapeutic use
- Abstract
Background: Switch maintenance is an effective strategy in the treatment of advanced Non-Small Cell Lung Cancer (NSCLC). Pazopanib is an oral, multi-targeted tyrosine kinase inhibitor (TKI). EORTC 08092 evaluated pazopanib given as maintenance treatment following standard first line platinum-based chemotherapy in patients with advanced NSCLC., Methods: Patients with non-progressive disease after 4-6 cycles of chemotherapy were randomised to receive either pazopanib 800mg/day or matched placebo until progression or unacceptable toxicity. The primary end-point was overall survival and secondary end-points were progression-free survival (PFS) and safety., Results: A total of 600 patients were planned to be randomised. The trial was prematurely stopped following an early interim analysis, after 102 patients were randomised to pazopanib (n=50) or placebo (n=52). Median age was 64years in both arms. Median overall survival was 17.4 months for pazopanib and 12.3 months for placebo (adjusted hazard ratio (HR) 0.72 [95% confidence interval (CI) 0.40-1.28]; p=0.257). Median PFS was 4.3 months versus 3.2 months (HR 0.67, [95% CI 0.43-1.03], p=0.068). PFS rates at 4 months were 56% and 45% respectively. The majority of treatment-related adverse events (AEs) were grade 1-2. Grade 3-4 AEs (pazopanib versus placebo) were hypertension (38% versus 8%), neutropenia (8% versus 0%), and elevated SGPT (6% versus 0%). Of the patients randomised to pazopanib, 22% withdrew due to a treatment-related AE., Conclusions: Switch maintenance with pazopanib following platinum-based chemotherapy in advanced NSCLC patients had limited side-effects. This study was stopped due to lack of efficacy by stringent criteria for PFS at a futility interim analysis., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
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- 2015
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41. Bone-targeted agents in the treatment of lung cancer.
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Silva SC, Wilson C, and Woll PJ
- Abstract
Over a third of patients with lung cancer will develop bone metastases during the course of their disease, resulting in symptoms of pain and immobility, and skeletal-related events (SREs) such as fracture, hypercalcaemia, surgery or radiotherapy to bones, and malignant spinal cord compression. These reduce quality of life and increase mortality. Preclinical research has identified the interactions between tumour cells and bone that are key to tumour cell survival and associated osteolysis. These data have led to the development of drugs to prevent osteoclast-mediated bone breakdown, such as zoledronic acid and denosumab, which are now licensed for use in patients with bone metastases from solid tumours. Both zoledronic acid and denosumab reduce the risk of SREs and increase time to first SRE, with minimal side effects. In addition, denosumab improved survival in patients with lung cancer compared with zoledronic acid. Ongoing trials are testing whether these drugs can prevent the development of bone metastases from lung cancer. New bone-targeted agents showing promise in breast and prostate cancer include radium-223, cabozantinib and Src inhibitors. These agents require further evaluation in patients with lung cancer.
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- 2015
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42. Cannabis smoking and lung cancer risk: Pooled analysis in the International Lung Cancer Consortium.
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Zhang LR, Morgenstern H, Greenland S, Chang SC, Lazarus P, Teare MD, Woll PJ, Orlow I, Cox B, Brhane Y, Liu G, and Hung RJ
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- Case-Control Studies, Humans, Risk, Adenocarcinoma etiology, Carcinoma, Squamous Cell etiology, Lung Neoplasms etiology, Marijuana Smoking adverse effects
- Abstract
To investigate the association between cannabis smoking and lung cancer risk, data on 2,159 lung cancer cases and 2,985 controls were pooled from 6 case-control studies in the US, Canada, UK, and New Zealand within the International Lung Cancer Consortium. Study-specific associations between cannabis smoking and lung cancer were estimated using unconditional logistic regression adjusting for sociodemographic factors, tobacco smoking status and pack-years; odds-ratio estimates were pooled using random effects models. Subgroup analyses were done for sex, histology and tobacco smoking status. The shapes of dose-response associations were examined using restricted cubic spline regression. The overall pooled OR for habitual versus nonhabitual or never users was 0.96 (95% CI: 0.66-1.38). Compared to nonhabitual or never users, the summary OR was 0.88 (95%CI: 0.63-1.24) for individuals who smoked 1 or more joint-equivalents of cannabis per day and 0.94 (95%CI: 0.67-1.32) for those consumed at least 10 joint-years. For adenocarcinoma cases the ORs were 1.73 (95%CI: 0.75-4.00) and 1.74 (95%CI: 0.85-3.55), respectively. However, no association was found for the squamous cell carcinoma based on small numbers. Weak associations between cannabis smoking and lung cancer were observed in never tobacco smokers. Spline modeling indicated a weak positive monotonic association between cumulative cannabis use and lung cancer, but precision was low at high exposure levels. Results from our pooled analyses provide little evidence for an increased risk of lung cancer among habitual or long-term cannabis smokers, although the possibility of potential adverse effect for heavy consumption cannot be excluded., (© 2014 UICC.)
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- 2015
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43. First-line anthracycline-based chemotherapy for angiosarcoma and other soft tissue sarcoma subtypes: pooled analysis of eleven European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group trials.
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Young RJ, Natukunda A, Litière S, Woll PJ, Wardelmann E, and van der Graaf WT
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- Adolescent, Adult, Aged, Female, Hemangiosarcoma drug therapy, Hemangiosarcoma mortality, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Prognosis, Prospective Studies, Randomized Controlled Trials as Topic, Sarcoma mortality, Young Adult, Antibiotics, Antineoplastic therapeutic use, Doxorubicin therapeutic use, Sarcoma drug therapy
- Abstract
Background: Angiosarcoma is a rare subtype of soft tissue sarcoma (STS). Doxorubicinis the standard first-line chemotherapy for advanced STS. It is not known whether angiosarcoma response to anthracycline-based chemotherapy is different to other STS subtypes., Methods: Pooled data were analysed from 11 prospective randomised and non-randomized European Organisation for Research and Treatment of Cancer (EORTC) clinical trials of first-line anthracycline-based chemotherapy for advanced STS. Baseline patient characteristics, chemotherapy response, progression free survival (PFS) and overall survival (OS) of angiosarcoma patients were compared with other STS patients. Analysis was performed to identify factors prognostic for angiosarcoma response to chemotherapy, PFS and OS., Results: With a median follow-up of 4.2 years, data from 108 locally advanced and metastatic angiosarcoma patients and 2557 patients with other STS histologies were analysed. 25% of angiosarcoma patients had a complete or partial response to chemotherapy compared to 21% for other STS histotypes. The median PFS was 4.9 months and OS 9.9 months, which were not significantly different from other STS histotypes. In univariate analysis, bone metastases were an adverse prognostic factor for OS (hazard ratio (HR) 1.66, 95% confidence interval (CI) 1.03–2.67; p = 0.036). Tumour grade was as an adverse prognostic factor for PFS (HR 1.72, 95% CI 1.01–2.92; p = 0.044) and OS (HR 2.03; 95% CI 1.16–3.56; p = 0.011). Compared to single agent anthracyclines, doxorubicin + ifosfamide was associated with improved PFS (HR 0.53, 95% CI 0.33–0.86; p = 0.010) and OS (HR 0.53, 95% CI 0.32–0.90; p = 0.018)., Conclusions: Angiosarcoma response and survival following first-line anthracycline-based chemotherapy was similar to other STS histotypes. Our analysis provides a useful measure of angiosarcoma response to chemotherapy for comparison with future clinical trials.
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- 2014
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44. Angiogenic growth factor expression in benign and malignant vascular tumours.
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Young RJ, Fernando M, Hughes D, Brown NJ, and Woll PJ
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- Breast Neoplasms metabolism, Breast Neoplasms pathology, Endothelium, Vascular metabolism, Endothelium, Vascular pathology, Female, Fibroblast Growth Factor 2 metabolism, Granuloma, Pyogenic metabolism, Granuloma, Pyogenic pathology, Hemangioma pathology, Hemangiosarcoma pathology, Hepatocyte Growth Factor metabolism, Humans, Receptor, Fibroblast Growth Factor, Type 1 metabolism, Receptor, Notch1 metabolism, Receptor, TIE-2 metabolism, Soft Tissue Neoplasms, Vascular Endothelial Growth Factor A metabolism, Angiogenic Proteins metabolism, Hemangioma metabolism, Hemangiosarcoma metabolism
- Abstract
Angiosarcomas are rare malignant vascular tumours. Angiosarcoma expression of vascular endothelial growth factor (VEGF) has previously been reported, but angiosarcoma expression of other angiogenic growth factors has not been systematically studied. Non-VEGF angiogenic growth factors are a potential mechanism of resistance to VEGF-targeted therapy, but they also represent potential therapeutic targets. Immunohistochemistry analysis evaluated the expression of 13 angiogenic growth factors and receptors in 27 separate benign and malignant archived human vascular tumour samples. The expression of 55 angiogenesis-related proteins was subsequently profiled in five fresh human angiosarcoma tumour samples using antibody arrays. Angiosarcomas expressed a variety of angiogenic growth factors. Significantly higher levels of Notch1 were detected compared with benign haemangiomas (p=0.033), but lower levels of basic fibroblast growth factor (bFGF) compared to benign haemangiomas (p=0.07) and inflammatory vascular lesions (p=0.009). Vascular tumour expression of FGF receptor (FGFR)-1 correlated with angiopoietin (Ang)-2, Tie2, hepatocyte growth factor (HGF) and Notch1 expression (p=0.001, p=0.001, p<0.001 and p<0.001 respectively). Notch1 also correlated with Tie2 expression (p=0.004). In conclusion, angiosarcomas express multiple angiogenic growth factors. Treatments could be targeted at individual angiogenic growth factors. However, our findings provide a rationale for combination therapy, or for treatments that target common downstream signalling intermediaries, such as Akt, mTOR or ERK., (Copyright © 2014 Elsevier Inc. All rights reserved.)
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- 2014
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45. Delaying skeletal-related events in a randomized phase 3 study of denosumab versus zoledronic acid in patients with advanced cancer: an analysis of data from patients with solid tumors.
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Henry D, Vadhan-Raj S, Hirsh V, von Moos R, Hungria V, Costa L, Woll PJ, Scagliotti G, Smith G, Feng A, Jun S, Dansey R, and Yeh H
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- Adolescent, Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Humanized administration & dosage, Bone Density Conservation Agents administration & dosage, Bone Neoplasms physiopathology, Bone Resorption prevention & control, Denosumab, Diphosphonates administration & dosage, Disease Progression, Double-Blind Method, Female, Humans, Imidazoles administration & dosage, Kaplan-Meier Estimate, Male, Middle Aged, Multiple Myeloma pathology, Neoplasms physiopathology, Pain drug therapy, Pain prevention & control, Treatment Outcome, Zoledronic Acid, Antibodies, Monoclonal, Humanized therapeutic use, Bone Density Conservation Agents therapeutic use, Bone Neoplasms secondary, Bone Resorption drug therapy, Diphosphonates therapeutic use, Imidazoles therapeutic use, Neoplasms pathology
- Abstract
Purpose: Bone complications of metastatic disease, including skeletal-related events (SREs), impair patients' functioning and quality of life. In a randomized, phase 3 trial of 1,776 patients with metastases from solid tumors (except breast or prostate) or multiple myeloma, denosumab was non-inferior to zoledronic acid (ZA) in delaying or preventing SREs. This ad hoc analysis reports outcomes in the subgroup of 1,597 patients with solid tumors, excluding patients with multiple myeloma., Methods: Patients received monthly subcutaneous denosumab 120 mg or intravenous ZA 4 mg, adjusted for creatinine clearance, with calcium and vitamin D supplementation recommended. Endpoints included times to first on-study SRE, first-and-subsequent SREs, and pain worsening., Results: Denosumab significantly delayed time to first on-study SRE compared with ZA (HR, 0.81; 95 % CI, 0.68-0.96) and time to first-and-subsequent SREs (RR, 0.85; 95 % CI, 0.72-1.00). Denosumab also significantly delayed time to development of moderate or severe pain (HR, 0.81; 95 % CI, 0.66-1.00), pain worsening (HR, 0.83; 95 % CI, 0.71-0.97), and worsening pain interference in patients with no/mild baseline pain (HR, 0.77; 95 % CI, 0.61-0.96). Adverse event rates were 96 % in both groups. Grade 3 or 4 hypocalcemia, mostly without clinical sequelae, was more frequent in denosumab-treated patients (denosumab 4 %, ZA 2 %). Osteonecrosis of the jaw occurred infrequently (denosumab 0.8 %, ZA 1.1 %)., Conclusions: Denosumab was more effective in delaying or preventing SREs in patients with bone metastases from solid tumors and also prevented pain progression compared to ZA in this ad hoc analysis.
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- 2014
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46. Vascular-targeted agents for the treatment of angiosarcoma.
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Young RJ, Woll PJ, Staton CA, Reed MW, and Brown NJ
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- Antibodies, Monoclonal, Humanized pharmacology, Axitinib, Bevacizumab, Cell Death drug effects, Cell Differentiation drug effects, Cell Line, Tumor, Cell Movement drug effects, Doxorubicin pharmacology, Everolimus, Hemangiosarcoma metabolism, Hemangiosarcoma pathology, Humans, Imidazoles pharmacology, Indazoles pharmacology, Neovascularization, Pathologic drug therapy, Neovascularization, Pathologic metabolism, Neovascularization, Pathologic pathology, Paclitaxel pharmacology, Protein Array Analysis, Sirolimus analogs & derivatives, Sirolimus pharmacology, Vascular Endothelial Growth Factor A antagonists & inhibitors, Vascular Endothelial Growth Factor A metabolism, Angiogenesis Inhibitors pharmacology, Hemangiosarcoma blood supply, Hemangiosarcoma drug therapy
- Abstract
Purpose: Angiosarcomas are rare, aggressive vascular tumours known to express vascular endothelial growth factor (VEGF), a key pro-angiogenic growth factor. The aim of this study was to determine the potential effects of vascular-targeted agents for the treatment of angiosarcoma, using two human cutaneous angiosarcoma cell lines (ASM and ISO-HAS), and human dermal microvascular endothelial cells (HuDMECs) for comparison., Methods: Protein arrays were used to assess the expression of angiogenesis-related proteins, and potential drug targets were assessed by ELISA and Western blotting. Response to vascular-targeted agents, including bevacizumab an anti-VEGF antibody, axitinib a VEGF-receptor tyrosine kinase inhibitor, everolimus an mTOR inhibitor, selumetinib a MEK inhibitor and vadimezan a vascular-disrupting agent were compared in functional in vitro cellular assays, including viability, differentiation and migration assays., Results: ASM and ISO-HAS cells expressed a broad range of pro-angiogenic growth factors. ASM and ISO-HAS VEGF expression was significantly increased (p = 0.029) compared with HuDMECs. Striking responses were seen to vadimezan with an IC50 of 90 and 150 μg/ml for ASM and ISO-HAS cells, respectively. Selumetinib inhibited ASM with an IC50 of 1,750 ng/ml, but was not effective in ISO-HAS. Everolimus reduced both ASM and ISO-HAS viable cell counts by 20 % (p < 0.001). Minimal responses were observed to bevacizumab and axitinib in assays with ASM and ISO-HAS cells., Conclusions: Further studies are warranted to investigate mTOR inhibitors, MEK inhibitors and vascular-disrupting agents for the treatment of angiosarcoma.
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- 2014
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47. Randomized phase II study of three doses of the integrin inhibitor cilengitide versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer.
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Manegold C, Vansteenkiste J, Cardenal F, Schuette W, Woll PJ, Ulsperger E, Kerber A, Eckmayr J, and von Pawel J
- Subjects
- Adult, Aged, Aged, 80 and over, Antineoplastic Agents adverse effects, Disease-Free Survival, Docetaxel, Female, Humans, Male, Middle Aged, Snake Venoms adverse effects, Taxoids administration & dosage, Taxoids adverse effects, Antineoplastic Agents administration & dosage, Carcinoma, Non-Small-Cell Lung drug therapy, Integrins antagonists & inhibitors, Lung Neoplasms drug therapy, Snake Venoms administration & dosage
- Abstract
Introduction: This multicenter, open-label, phase II study was carried out to compare the efficacy and safety of cilengitide (EMD 121974), a selective inhibitor of the cell-surface integrins αVβ3 and αVβ5, with that of docetaxel in patients with advanced non-small-cell lung cancer (NSCLC)., Methods: Patients (n = 140) with advanced NSCLC who had failed first-line chemotherapy were randomized to cilengitide 240, 400, or 600 mg/m(2) twice weekly, or docetaxel 75 mg/m(2) once every 3 weeks for eight cycles. Non-progressing patients could continue cilengitide for up to 1 year. The primary endpoint was progression-free survival (PFS). No statistical tests were performed since the study was exploratory in nature and the number of patients enrolled was relatively small., Results: Median PFS was 54, 63, 63, and 67 days for cilengitide 240, 400, and 600 mg/m(2), and docetaxel 75 mg/m(2), respectively. One-year survival rates were 13 %, 13 %, 29 %, and 27 %, respectively. The response rate (partial response only) with docetaxel was 15 %. No responses were reported in any cilengitide arm. The most frequent grade 3/4 treatment-related adverse events in the docetaxel group were leukopenia and neutropenia (experienced by 13 % of patients). Hematologic toxicity of this severity did not occur in cilengitide-treated patients., Conclusion: With the highest dose of cilengitide (600 mg/m(2)), median PFS and 1-year survival were similar to those in patients treated with docetaxel 75 mg/m(2) and there were fewer grade 3/4 treatment-related adverse events.
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- 2013
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48. Prognostic factors in adolescents and young adults (AYA) with high risk soft tissue sarcoma (STS) treated by adjuvant chemotherapy: a study based on pooled European Organisation for Research and Treatment of Cancer (EORTC) clinical trials 62771 and 62931.
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Kasper B, Ouali M, van Glabbeke M, Blay JY, Bramwell VH, Woll PJ, Hohenberger P, and Schöffski P
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- Adolescent, Adult, Age Factors, Chemotherapy, Adjuvant, Combined Modality Therapy, Female, Humans, Male, Prognosis, Retrospective Studies, Risk Factors, Sarcoma pathology, Sarcoma surgery, Survival Analysis, Treatment Outcome, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Sarcoma drug therapy
- Abstract
Background: We conducted a retrospective study, pooling data from two clinical trials in high risk soft tissue sarcoma (STS) patients, with the objective of comparing two different age groups: 15-29 years (adolescents and young adults (AYA) population) and ≥ 30 years. The aim was to determine prognostic factors for the AYA population., Methods: Patients selected for analysis were treated in two randomised trials of adjuvant chemotherapy in STS (European Organisation for Research and Treatment of Cancer (EORTC) 62771 and 62931). A total of 793 patients were included with a median follow-up (FU) of 8.74 years (AYA population: n=161, median FU 9.46 years; patients ≥ 30 years: n=632, median FU 8.62 years). Study endpoints were overall survival (OS) and relapse-free survival (RFS). The variables of the multivariate analysis were gender, subtype and grade, tumour size and localisation (limb versus other), absence or presence of local recurrence and treatment (control arm versus adjuvant chemotherapy)., Results: Patients' characteristics were globally similar with two exceptions, histological subtype (p=0.0043) and tumour size (p<.0001). The commonest sarcoma subtype in the AYA population was synovial sarcoma (29%), whereas leiomyosarcoma (18%), malignant fibrous histiocytoma (MFH, presently being termed undifferentiated pleomorphic sarcoma (UPS), 16%) and liposarcoma (15%) were more frequent in patients ≥ 30 years. For OS, independent favourable prognostic factors were low grade and small tumour size for both groups; radical resection and MFH or liposarcoma subtype were favourable factors for patients ≥ 30 years only. For RFS, favourable prognostic factors were small tumour size and low grade for both groups; tumour location in the extremities was a favourable factor for the AYA population only, whereas radical resection and adjuvant chemotherapy treatment were favourable factors for patients ≥ 30y ears only., Conclusions: Significant differences could be found concerning prognostic factors between the AYA population and older patients. Interestingly, adjuvant chemotherapy was associated with improved RFS only in patients ≥ 30 years. The results may have further implications for the treatment of STS patients in different age groups, as well as the design of future clinical trials., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2013
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49. First-line erlotinib in patients with advanced non-small-cell lung cancer unsuitable for chemotherapy (TOPICAL): a double-blind, placebo-controlled, phase 3 trial.
- Author
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Lee SM, Khan I, Upadhyay S, Lewanski C, Falk S, Skailes G, Marshall E, Woll PJ, Hatton M, Lal R, Jones R, Toy E, Chao D, Middleton G, Bulley S, Ngai Y, Rudd R, Hackshaw A, and Boshoff C
- Subjects
- Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Non-Small-Cell Lung pathology, Disease-Free Survival, Double-Blind Method, Drug-Related Side Effects and Adverse Reactions chemically induced, Drug-Related Side Effects and Adverse Reactions classification, ErbB Receptors, Erlotinib Hydrochloride, Female, Humans, Kaplan-Meier Estimate, Lung Neoplasms pathology, Male, Neoplasm Staging, Protein Kinase Inhibitors adverse effects, Quinazolines adverse effects, Treatment Outcome, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Neoplasms drug therapy, Protein Kinase Inhibitors administration & dosage, Quinazolines administration & dosage
- Abstract
Background: Many patients with advanced non-small-cell lung cancer (NSCLC) receive only active supportive care because of poor performance status or presence of several comorbidities. We investigated whether erlotinib improves clinical outcome in these patients., Methods: TOPICAL was a double-blind, randomised, placebo-controlled, phase 3 trial, done at 78 centres in the UK. Eligibility criteria were newly diagnosed, pathologically confirmed NSCLC; stage IIIb or IV; chemotherapy naive; no symptomatic brain metastases; deemed unsuitable for chemotherapy because of poor (≥2) Eastern Cooperative Oncology Group performance status or presence of several comorbidities, or both; and estimated life expectancy of at least 8 weeks. Patients were randomly assigned (by phone call, in a 1:1 ratio, stratified by disease stage, performance status, smoking history, and centre, block size 10) to receive oral placebo or erlotinib (150 mg per day) until disease progression or unacceptable toxicity. Investigators, clinicians, and patients were masked to assignment. The primary endpoint was overall survival. Analyses were by intention to treat, and prespecified subgroup analyses included development of a rash due to erlotinib within 28 days of starting treatment. This study is registered, number ISRCTN 77383050., Findings: Between April 14, 2005, and April 1, 2009, we randomly assigned 350 patients to receive erlotinib and 320 to receive placebo. We followed up patients until March 31, 2011. 657 patients died; median overall survival did not differ between groups (erlotinib, 3·7 months, 95% CI 3·2-4·2, vs placebo, 3·6 months, 3·2-3·9; unadjusted hazard ratio [HR] 0·94, 95% CI 0·81-1·10, p=0·46). 59% (178 of 302) of patients assigned erlotinib and who were assessable at 1 month developed first-cycle rash, which was the only independent factor associated with overall survival. Patients with first-cycle rash had better overall survival (HR 0·76, 95% CI 0·63-0·92, p=0·0058), compared with placebo. Compared with placebo, overall survival seemed to be worse in the group that did not develop first-cycle rash (1·30, 1·05-1·61, p=0·017). Grade 3 or 4 diarrhoea was more common with erlotinib than placebo (8% [28 of 334] vs 1% [four of 313], p=0·0001), as was high-grade rash (23% [79 of 334] vs 2% [five of 313], p<0·0001); other adverse events were much the same between groups., Interpretation: Patients with NSCLC who are deemed unsuitable for chemotherapy could be given erlotinib. Patients who develop a first-cycle rash should continue to receive erlotinib, whereas those who do not have a rash after 28 days should discontinue erlotinib, because of the possibility of decreased survival., Funding: Cancer Research UK, Roche., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2012
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50. Adjuvant chemotherapy with doxorubicin, ifosfamide, and lenograstim for resected soft-tissue sarcoma (EORTC 62931): a multicentre randomised controlled trial.
- Author
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Woll PJ, Reichardt P, Le Cesne A, Bonvalot S, Azzarelli A, Hoekstra HJ, Leahy M, Van Coevorden F, Verweij J, Hogendoorn PC, Ouali M, Marreaud S, Bramwell VH, and Hohenberger P
- Subjects
- Adolescent, Adult, Aged, Chemotherapy, Adjuvant, Doxorubicin administration & dosage, Female, Granulocyte Colony-Stimulating Factor administration & dosage, Humans, Ifosfamide administration & dosage, Lenograstim, Male, Middle Aged, Recombinant Proteins administration & dosage, Sarcoma mortality, Sarcoma pathology, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Sarcoma drug therapy
- Abstract
Background: The effect of adjuvant chemotherapy on survival for resected soft-tissue sarcoma remains unknown. We investigated the effect of intensive adjuvant chemotherapy on survival in patients after resection of high-risk soft-tissue sarcomas., Methods: In this multicentre randomised trial, patients with macroscopically resected, Trojani grade II-III soft-tissue sarcomas at any site, no metastases, performance status lower than 2 and aged between 16 and 70 years were eligible within 4 weeks of definitive surgery. Patients were randomly assigned to receive adjuvant chemotherapy or no chemotherapy (control group). Randomisation was done with a minimisation technique, stratified by hospital, site of primary tumour, tumour size, planned radiotherapy, and isolated limb perfusion therapy. Chemotherapy consisted of five cycles of doxorubicin 75 mg/m(2), ifosfamide 5 g/m(2), and lenograstim every 3 weeks. Patients in both groups received radiotherapy if the resection was marginal or the tumour recurrent. The primary endpoint was overall survival and analyses were done by intention to treat. The final results are presented. This trial is registered with ClinicalTrials.gov, NCT00002641., Findings: Between February, 1995, and December, 2003, 351 patients were randomly assigned to the adjuvant chemotherapy group (175 patients) or to the control group (176). 258 (73%) of 351 patients received radiotherapy, 129 in each group. Overall survival did not differ significantly between groups (hazard ratio [HR] 0·94 [95% CI 0·68-1·31], p=0·72) nor did relapse-free survival (HR 0·91 [0·67-1·22], p=0·51). 5-year overall survival rate was 66·5% (58·8-73·0) in the chemotherapy group and 67·8% (60·3-74·2) in the control group. Chemotherapy was well tolerated, with 130 (80%) of 163 patients who started it completing all five cycles. 16 (10%) patients had grade 3 or 4 fever or infection, but no deaths due to toxic effects were recorded., Interpretation: Adjuvant chemotherapy with doxorubicin and ifosfamide in resected soft-tissue sarcoma showed no benefit in relapse-free survival or overall survival. Future studies should focus on patients with larger, grade III, and extremity sarcomas., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2012
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