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Publisher: Oxford University Press   (Total: 370 journals)

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Showing 1 - 200 of 370 Journals sorted alphabetically
Acta Biochimica et Biophysica Sinica     Hybrid Journal   (Followers: 6, SJR: 0.881, h-index: 38)
Adaptation     Hybrid Journal   (Followers: 8, SJR: 0.111, h-index: 4)
Aesthetic Surgery J.     Hybrid Journal   (Followers: 6, SJR: 1.538, h-index: 35)
African Affairs     Hybrid Journal   (Followers: 60, SJR: 1.512, h-index: 46)
Age and Ageing     Hybrid Journal   (Followers: 84, SJR: 1.611, h-index: 107)
Alcohol and Alcoholism     Hybrid Journal   (Followers: 15, SJR: 0.935, h-index: 80)
American Entomologist     Full-text available via subscription   (Followers: 6)
American Historical Review     Hybrid Journal   (Followers: 131, SJR: 0.652, h-index: 43)
American J. of Agricultural Economics     Hybrid Journal   (Followers: 41, SJR: 1.441, h-index: 77)
American J. of Epidemiology     Hybrid Journal   (Followers: 159, SJR: 3.047, h-index: 201)
American J. of Hypertension     Hybrid Journal   (Followers: 23, SJR: 1.397, h-index: 111)
American J. of Jurisprudence     Hybrid Journal   (Followers: 16)
American J. of Legal History     Full-text available via subscription   (Followers: 5, SJR: 0.151, h-index: 7)
American Law and Economics Review     Hybrid Journal   (Followers: 25, SJR: 0.824, h-index: 23)
American Literary History     Hybrid Journal   (Followers: 12, SJR: 0.185, h-index: 22)
Analysis     Hybrid Journal   (Followers: 24)
Annals of Botany     Hybrid Journal   (Followers: 35, SJR: 1.912, h-index: 124)
Annals of Occupational Hygiene     Hybrid Journal   (Followers: 26, SJR: 0.837, h-index: 57)
Annals of Oncology     Hybrid Journal   (Followers: 47, SJR: 4.362, h-index: 173)
Annals of the Entomological Society of America     Full-text available via subscription   (Followers: 8, SJR: 0.642, h-index: 53)
Annals of Work Exposures and Health     Hybrid Journal  
AoB Plants     Open Access   (Followers: 3, SJR: 0.78, h-index: 10)
Applied Economic Perspectives and Policy     Hybrid Journal   (Followers: 19, SJR: 0.884, h-index: 31)
Applied Linguistics     Hybrid Journal   (Followers: 51, SJR: 1.749, h-index: 63)
Applied Mathematics Research eXpress     Hybrid Journal   (Followers: 1, SJR: 0.779, h-index: 11)
Arbitration Intl.     Full-text available via subscription   (Followers: 20)
Arbitration Law Reports and Review     Hybrid Journal   (Followers: 13)
Archives of Clinical Neuropsychology     Hybrid Journal   (Followers: 26, SJR: 0.96, h-index: 71)
Aristotelian Society Supplementary Volume     Hybrid Journal   (Followers: 2, SJR: 0.102, h-index: 20)
Arthropod Management Tests     Hybrid Journal   (Followers: 2)
Astronomy & Geophysics     Hybrid Journal   (Followers: 47, SJR: 0.144, h-index: 15)
Behavioral Ecology     Hybrid Journal   (Followers: 48, SJR: 1.698, h-index: 92)
Bioinformatics     Hybrid Journal   (Followers: 246, SJR: 4.643, h-index: 271)
Biology Methods and Protocols     Hybrid Journal  
Biology of Reproduction     Full-text available via subscription   (Followers: 9, SJR: 1.646, h-index: 149)
Biometrika     Hybrid Journal   (Followers: 19, SJR: 2.801, h-index: 90)
BioScience     Hybrid Journal   (Followers: 28, SJR: 2.374, h-index: 154)
Bioscience Horizons : The National Undergraduate Research J.     Open Access   (Followers: 1, SJR: 0.213, h-index: 9)
Biostatistics     Hybrid Journal   (Followers: 16, SJR: 1.955, h-index: 55)
BJA : British J. of Anaesthesia     Hybrid Journal   (Followers: 143, SJR: 2.314, h-index: 133)
BJA Education     Hybrid Journal   (Followers: 66, SJR: 0.272, h-index: 20)
Brain     Hybrid Journal   (Followers: 60, SJR: 6.097, h-index: 264)
Briefings in Bioinformatics     Hybrid Journal   (Followers: 45, SJR: 4.086, h-index: 73)
Briefings in Functional Genomics     Hybrid Journal   (Followers: 4, SJR: 1.771, h-index: 50)
British J. for the Philosophy of Science     Hybrid Journal   (Followers: 34, SJR: 1.267, h-index: 38)
British J. of Aesthetics     Hybrid Journal   (Followers: 25, SJR: 0.217, h-index: 18)
British J. of Criminology     Hybrid Journal   (Followers: 522, SJR: 1.373, h-index: 62)
British J. of Social Work     Hybrid Journal   (Followers: 82, SJR: 0.771, h-index: 53)
British Medical Bulletin     Hybrid Journal   (Followers: 7, SJR: 1.391, h-index: 84)
British Yearbook of Intl. Law     Hybrid Journal   (Followers: 27)
Bulletin of the London Mathematical Society     Hybrid Journal   (Followers: 3, SJR: 1.474, h-index: 31)
Cambridge J. of Economics     Hybrid Journal   (Followers: 58, SJR: 0.957, h-index: 59)
Cambridge J. of Regions, Economy and Society     Hybrid Journal   (Followers: 11, SJR: 1.067, h-index: 22)
Cambridge Quarterly     Hybrid Journal   (Followers: 11, SJR: 0.1, h-index: 7)
Capital Markets Law J.     Hybrid Journal  
Carcinogenesis     Hybrid Journal   (Followers: 2, SJR: 2.439, h-index: 167)
Cardiovascular Research     Hybrid Journal   (Followers: 11, SJR: 2.897, h-index: 175)
Cerebral Cortex     Hybrid Journal   (Followers: 40, SJR: 4.827, h-index: 192)
CESifo Economic Studies     Hybrid Journal   (Followers: 16, SJR: 0.501, h-index: 19)
Chemical Senses     Hybrid Journal   (Followers: 1, SJR: 1.436, h-index: 76)
Children and Schools     Hybrid Journal   (Followers: 6, SJR: 0.211, h-index: 18)
Chinese J. of Comparative Law     Hybrid Journal   (Followers: 3)
Chinese J. of Intl. Law     Hybrid Journal   (Followers: 21, SJR: 0.737, h-index: 11)
Chinese J. of Intl. Politics     Hybrid Journal   (Followers: 8, SJR: 1.238, h-index: 15)
Christian Bioethics: Non-Ecumenical Studies in Medical Morality     Hybrid Journal   (Followers: 11, SJR: 0.191, h-index: 8)
Classical Receptions J.     Hybrid Journal   (Followers: 19, SJR: 0.1, h-index: 3)
Clinical Infectious Diseases     Hybrid Journal   (Followers: 58, SJR: 4.742, h-index: 261)
Clinical Kidney J.     Open Access   (Followers: 4, SJR: 0.338, h-index: 19)
Community Development J.     Hybrid Journal   (Followers: 24, SJR: 0.47, h-index: 28)
Computer J.     Hybrid Journal   (Followers: 7, SJR: 0.371, h-index: 47)
Conservation Physiology     Open Access   (Followers: 2)
Contemporary Women's Writing     Hybrid Journal   (Followers: 11, SJR: 0.111, h-index: 3)
Contributions to Political Economy     Hybrid Journal   (Followers: 6, SJR: 0.313, h-index: 10)
Critical Values     Full-text available via subscription  
Current Legal Problems     Hybrid Journal   (Followers: 26)
Current Zoology     Full-text available via subscription   (SJR: 0.999, h-index: 20)
Database : The J. of Biological Databases and Curation     Open Access   (Followers: 11, SJR: 1.068, h-index: 24)
Digital Scholarship in the Humanities     Hybrid Journal   (Followers: 12)
Diplomatic History     Hybrid Journal   (Followers: 18, SJR: 0.296, h-index: 22)
DNA Research     Open Access   (Followers: 4, SJR: 2.42, h-index: 77)
Dynamics and Statistics of the Climate System     Open Access   (Followers: 3)
Early Music     Hybrid Journal   (Followers: 14, SJR: 0.124, h-index: 11)
Economic Policy     Hybrid Journal   (Followers: 59, SJR: 2.052, h-index: 52)
ELT J.     Hybrid Journal   (Followers: 25, SJR: 1.26, h-index: 23)
English Historical Review     Hybrid Journal   (Followers: 48, SJR: 0.311, h-index: 10)
English: J. of the English Association     Hybrid Journal   (Followers: 13, SJR: 0.144, h-index: 3)
Environmental Entomology     Full-text available via subscription   (Followers: 11, SJR: 0.791, h-index: 66)
Environmental Epigenetics     Open Access   (Followers: 1)
Environmental History     Hybrid Journal   (Followers: 26, SJR: 0.197, h-index: 25)
EP-Europace     Hybrid Journal   (Followers: 2, SJR: 2.201, h-index: 71)
Epidemiologic Reviews     Hybrid Journal   (Followers: 10, SJR: 3.917, h-index: 81)
ESHRE Monographs     Hybrid Journal  
Essays in Criticism     Hybrid Journal   (Followers: 16, SJR: 0.1, h-index: 6)
European Heart J.     Hybrid Journal   (Followers: 49, SJR: 6.997, h-index: 227)
European Heart J. - Cardiovascular Imaging     Hybrid Journal   (Followers: 9, SJR: 2.044, h-index: 58)
European Heart J. - Cardiovascular Pharmacotherapy     Full-text available via subscription   (Followers: 1)
European Heart J. - Quality of Care and Clinical Outcomes     Hybrid Journal  
European Heart J. Supplements     Hybrid Journal   (Followers: 8, SJR: 0.152, h-index: 31)
European J. of Cardio-Thoracic Surgery     Hybrid Journal   (Followers: 8, SJR: 1.568, h-index: 104)
European J. of Intl. Law     Hybrid Journal   (Followers: 152, SJR: 0.722, h-index: 38)
European J. of Orthodontics     Hybrid Journal   (Followers: 4, SJR: 1.09, h-index: 60)
European J. of Public Health     Hybrid Journal   (Followers: 22, SJR: 1.284, h-index: 64)
European Review of Agricultural Economics     Hybrid Journal   (Followers: 12, SJR: 1.549, h-index: 42)
European Review of Economic History     Hybrid Journal   (Followers: 28, SJR: 0.628, h-index: 24)
European Sociological Review     Hybrid Journal   (Followers: 40, SJR: 2.061, h-index: 53)
Evolution, Medicine, and Public Health     Open Access   (Followers: 11)
Family Practice     Hybrid Journal   (Followers: 11, SJR: 1.048, h-index: 77)
Fems Microbiology Ecology     Hybrid Journal   (Followers: 8, SJR: 1.687, h-index: 115)
Fems Microbiology Letters     Hybrid Journal   (Followers: 20, SJR: 1.126, h-index: 118)
Fems Microbiology Reviews     Hybrid Journal   (Followers: 25, SJR: 7.587, h-index: 150)
Fems Yeast Research     Hybrid Journal   (Followers: 13, SJR: 1.213, h-index: 66)
Foreign Policy Analysis     Hybrid Journal   (Followers: 21, SJR: 0.859, h-index: 10)
Forestry: An Intl. J. of Forest Research     Hybrid Journal   (Followers: 16, SJR: 0.903, h-index: 44)
Forum for Modern Language Studies     Hybrid Journal   (Followers: 6, SJR: 0.108, h-index: 6)
French History     Hybrid Journal   (Followers: 31, SJR: 0.123, h-index: 10)
French Studies     Hybrid Journal   (Followers: 19, SJR: 0.119, h-index: 7)
French Studies Bulletin     Hybrid Journal   (Followers: 10, SJR: 0.102, h-index: 3)
Gastroenterology Report     Open Access   (Followers: 2)
Genome Biology and Evolution     Open Access   (Followers: 9, SJR: 3.22, h-index: 39)
Geophysical J. Intl.     Hybrid Journal   (Followers: 34, SJR: 1.839, h-index: 119)
German History     Hybrid Journal   (Followers: 25, SJR: 0.437, h-index: 13)
GigaScience     Open Access   (Followers: 3)
Global Summitry     Hybrid Journal  
Glycobiology     Hybrid Journal   (Followers: 14, SJR: 1.692, h-index: 101)
Health and Social Work     Hybrid Journal   (Followers: 48, SJR: 0.505, h-index: 40)
Health Education Research     Hybrid Journal   (Followers: 12, SJR: 0.814, h-index: 80)
Health Policy and Planning     Hybrid Journal   (Followers: 19, SJR: 1.628, h-index: 66)
Health Promotion Intl.     Hybrid Journal   (Followers: 21, SJR: 0.664, h-index: 60)
History Workshop J.     Hybrid Journal   (Followers: 26, SJR: 0.313, h-index: 20)
Holocaust and Genocide Studies     Hybrid Journal   (Followers: 23, SJR: 0.115, h-index: 13)
Human Molecular Genetics     Hybrid Journal   (Followers: 9, SJR: 4.288, h-index: 233)
Human Reproduction     Hybrid Journal   (Followers: 78, SJR: 2.271, h-index: 179)
Human Reproduction Update     Hybrid Journal   (Followers: 18, SJR: 4.678, h-index: 128)
Human Rights Law Review     Hybrid Journal   (Followers: 59, SJR: 0.7, h-index: 21)
ICES J. of Marine Science: J. du Conseil     Hybrid Journal   (Followers: 53, SJR: 1.233, h-index: 88)
ICSID Review     Hybrid Journal   (Followers: 9)
ILAR J.     Hybrid Journal   (Followers: 1, SJR: 1.099, h-index: 51)
IMA J. of Applied Mathematics     Hybrid Journal   (SJR: 0.329, h-index: 26)
IMA J. of Management Mathematics     Hybrid Journal   (Followers: 2, SJR: 0.351, h-index: 20)
IMA J. of Mathematical Control and Information     Hybrid Journal   (Followers: 2, SJR: 0.661, h-index: 28)
IMA J. of Numerical Analysis - advance access     Hybrid Journal   (SJR: 2.032, h-index: 44)
Industrial and Corporate Change     Hybrid Journal   (Followers: 8, SJR: 1.37, h-index: 81)
Industrial Law J.     Hybrid Journal   (Followers: 29, SJR: 0.184, h-index: 15)
Information and Inference     Free  
Integrative and Comparative Biology     Hybrid Journal   (Followers: 8, SJR: 1.911, h-index: 90)
Interacting with Computers     Hybrid Journal   (Followers: 10, SJR: 0.529, h-index: 59)
Interactive CardioVascular and Thoracic Surgery     Hybrid Journal   (Followers: 5, SJR: 0.743, h-index: 35)
Intl. Affairs     Hybrid Journal   (Followers: 51, SJR: 1.264, h-index: 53)
Intl. Data Privacy Law     Hybrid Journal   (Followers: 28)
Intl. Health     Hybrid Journal   (Followers: 5, SJR: 0.835, h-index: 15)
Intl. Immunology     Hybrid Journal   (Followers: 3, SJR: 1.613, h-index: 111)
Intl. J. for Quality in Health Care     Hybrid Journal   (Followers: 32, SJR: 1.593, h-index: 69)
Intl. J. of Constitutional Law     Hybrid Journal   (Followers: 59, SJR: 0.613, h-index: 19)
Intl. J. of Epidemiology     Hybrid Journal   (Followers: 137, SJR: 4.381, h-index: 145)
Intl. J. of Law and Information Technology     Hybrid Journal   (Followers: 4, SJR: 0.247, h-index: 8)
Intl. J. of Law, Policy and the Family     Hybrid Journal   (Followers: 28, SJR: 0.307, h-index: 15)
Intl. J. of Lexicography     Hybrid Journal   (Followers: 8, SJR: 0.404, h-index: 18)
Intl. J. of Low-Carbon Technologies     Open Access   (Followers: 1, SJR: 0.457, h-index: 12)
Intl. J. of Neuropsychopharmacology     Open Access   (Followers: 3, SJR: 1.69, h-index: 79)
Intl. J. of Public Opinion Research     Hybrid Journal   (Followers: 8, SJR: 0.906, h-index: 33)
Intl. J. of Refugee Law     Hybrid Journal   (Followers: 32, SJR: 0.231, h-index: 21)
Intl. J. of Transitional Justice     Hybrid Journal   (Followers: 13, SJR: 0.833, h-index: 12)
Intl. Mathematics Research Notices     Hybrid Journal   (Followers: 1, SJR: 2.052, h-index: 42)
Intl. Political Sociology     Hybrid Journal   (Followers: 31, SJR: 1.339, h-index: 19)
Intl. Relations of the Asia-Pacific     Hybrid Journal   (Followers: 17, SJR: 0.539, h-index: 17)
Intl. Studies Perspectives     Hybrid Journal   (Followers: 7, SJR: 0.998, h-index: 28)
Intl. Studies Quarterly     Hybrid Journal   (Followers: 38, SJR: 2.184, h-index: 68)
Intl. Studies Review     Hybrid Journal   (Followers: 18, SJR: 0.783, h-index: 38)
ISLE: Interdisciplinary Studies in Literature and Environment     Hybrid Journal   (Followers: 1, SJR: 0.155, h-index: 4)
ITNOW     Hybrid Journal   (Followers: 2, SJR: 0.102, h-index: 4)
J. of African Economies     Hybrid Journal   (Followers: 15, SJR: 0.647, h-index: 30)
J. of American History     Hybrid Journal   (Followers: 40, SJR: 0.286, h-index: 34)
J. of Analytical Toxicology     Hybrid Journal   (Followers: 13, SJR: 1.038, h-index: 60)
J. of Antimicrobial Chemotherapy     Hybrid Journal   (Followers: 12, SJR: 2.157, h-index: 149)
J. of Antitrust Enforcement     Hybrid Journal   (Followers: 1)
J. of Applied Poultry Research     Hybrid Journal   (Followers: 3, SJR: 0.563, h-index: 43)
J. of Biochemistry     Hybrid Journal   (Followers: 43, SJR: 1.341, h-index: 96)
J. of Chromatographic Science     Hybrid Journal   (Followers: 16, SJR: 0.448, h-index: 42)
J. of Church and State     Hybrid Journal   (Followers: 11, SJR: 0.167, h-index: 11)
J. of Competition Law and Economics     Hybrid Journal   (Followers: 34, SJR: 0.442, h-index: 16)
J. of Complex Networks     Hybrid Journal   (Followers: 1, SJR: 1.165, h-index: 5)
J. of Conflict and Security Law     Hybrid Journal   (Followers: 12, SJR: 0.196, h-index: 15)
J. of Consumer Research     Full-text available via subscription   (Followers: 41, SJR: 4.896, h-index: 121)
J. of Crohn's and Colitis     Hybrid Journal   (Followers: 9, SJR: 1.543, h-index: 37)
J. of Cybersecurity     Hybrid Journal   (Followers: 3)
J. of Deaf Studies and Deaf Education     Hybrid Journal   (Followers: 8, SJR: 0.69, h-index: 36)
J. of Design History     Hybrid Journal   (Followers: 15, SJR: 0.166, h-index: 14)
J. of Economic Entomology     Full-text available via subscription   (Followers: 6, SJR: 0.894, h-index: 76)
J. of Economic Geography     Hybrid Journal   (Followers: 39, SJR: 2.909, h-index: 69)
J. of Environmental Law     Hybrid Journal   (Followers: 23, SJR: 0.457, h-index: 20)
J. of European Competition Law & Practice     Hybrid Journal   (Followers: 18)
J. of Experimental Botany     Hybrid Journal   (Followers: 14, SJR: 2.798, h-index: 163)
J. of Financial Econometrics     Hybrid Journal   (Followers: 21, SJR: 1.314, h-index: 27)
J. of Global Security Studies     Hybrid Journal   (Followers: 3)
J. of Heredity     Hybrid Journal   (Followers: 4, SJR: 1.024, h-index: 76)
J. of Hindu Studies     Hybrid Journal   (Followers: 7, SJR: 0.186, h-index: 3)
J. of Hip Preservation Surgery     Open Access  
J. of Human Rights Practice     Hybrid Journal   (Followers: 20, SJR: 0.399, h-index: 10)
J. of Infectious Diseases     Hybrid Journal   (Followers: 40, SJR: 4, h-index: 209)
J. of Insect Science     Open Access   (Followers: 9, SJR: 0.388, h-index: 31)

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Journal Cover Annals of Oncology
  [SJR: 4.362]   [H-I: 173]   [47 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0923-7534 - ISSN (Online) 1569-8041
   Published by Oxford University Press Homepage  [370 journals]
  • BET inhibitors: a novel epigenetic approach
    • Authors: Doroshow DB; Eder JP, LoRusso PM.
      Abstract: AbstractEpigenetics has been defined as ‘the structural adaptation of chromosomal regions so as to register, signal or perpetuate altered activity states.’ Currently, several classes of anticancer drugs function at the epigenetic level, including inhibitors of DNA methyltransferase, histone deacetylase (HDAC), lysine-specific demethylase 1, zeste homolog 2, and bromodomain and extra-terminal motif (BET) proteins.BET proteins have multiple functions, including the initiation and elongation of transcription and cell cycle regulation. In recent years, inhibitors of BET proteins have been developed as anticancer agents. These inhibitors exhibit selectivity for tumor cells by preferentially binding to superenhancers, noncoding regions of DNA critical for the transcription of genes that determine a cell’s identity. Preclinical research on BET inhibitors has identified them as a potential means of targeting MYC.Early clinical trials with BET inhibitors have had mixed results, with few responses in both hematologic and solid tumors that tend to be short-lived. Toxicities have included severe, thrombocytopenia, fatigue, nausea, vomiting, and diarrhea; GI side-effects, fatigue, and low-grade dysgeusia have limited compliance. However, preclinical data suggest that BET inhibitors may have a promising future in combination with other agents. They appear to be able to overcome resistance to targeted agents and have strong synergy with immune checkpoint inhibitors as well as with multiple epigenetic agents, particularly HDAC inhibitors. In many instances, BET and HDAC inhibitors were synergistic at reduced doses, suggesting a potential means of avoiding the overlapping toxicities of the two drug classes.BET inhibitors provide a novel approach to epigenetic anticancer therapy. However, to date they appear to have limited efficacy as single agents. A focus on BET inhibitors in combination with other drugs such as targeted and/or as other epigenetic agents is warranted, due to limited monotherapy activity, including pharmacodynamic correlatives differential activity amongst select drug combinations.
      PubDate: 2017-07-21
       
  • Reply to the letter to the editor ‘Specific QOL scales that reflect
           toxicity-induced impairment are needed in RCTs’
    • Authors: Schuurhuizen CW; Braamse AJ, Konings IM, et al.
      Abstract: We would like to thank Procaccio and colleagues [1] for their helpful comments on our systematic review of the literature examining whether severe toxicity affects global quality of life (QOL) in patients with metastatic colorectal cancer (mCRC) receiving palliative systemic treatment in randomized controlled trials (RCTs) [2].
      PubDate: 2017-07-06
       
  • Prognostic significance of PD-L1 expression on circulating tumor cells in
           patients with head and neck squamous cell carcinoma
    • Authors: Strati AA; Koutsodontis GG, Papaxoinis GG, et al.
      Abstract: AbstractBackgroundSuccessful application of programmed death 1 (PD1) checkpoint inhibitors in the clinic may ultimately benefit from appropriate patient selection based upon predictive biomarkers. Molecular characterization of circulating tumor cells (CTC) is crucial for the investigation of molecular-targeted therapies while predictive biomarkers for response to PD1 checkpoint inhibitors are lacking. We sought to assess whether overexpression of PD-L1 in CTCs could be detected at baseline and at different timepoints during treatment in a prospective cohort of head and neck squamous cell carcinoma (HNSCC) patients and used to predict clinical outcome after treatment with curative intent.Patients and methodsWe developed a highly sensitive, specific and robust RT-qPCR assay for PD-L1 mRNA expression in EpCAM(+) CTCs. In a prospective cohort of 113 locally advanced HNSCC patients treated with curative intent we evaluated PD-L1 expression in the EpCAM(+) CTC fraction at baseline, after 2 cycles of induction chemotherapy (week 6) and at the end of concurrent chemoradiotherapy (week 15).ResultsPD-L1 overexpression was found in 24/94 (25.5%) patients at baseline, 8/34 (23.5%) after induction chemotherapy and 12/54 (22.2%) patients at the end of treatment. Patients with CTCs overexpressing PD-L1 at end of treatment had shorter progression-free survival (P = 0.001) and overall survival (P < 0.001). Multivariate analysis revealed that PD-L1 overexpression at end of treatment was independent prognostic factor for progression-free survival and overall survival. The absence of PD-L1 overexpression at the end of treatment was strongly associated with complete response with an odds ratio = 16.00 (95% CI = 2.76–92.72, P = 0.002).ConclusionsWe demonstrate that detection of CTCs overexpressing PD-L1 is feasible and may provide important prognostic information in HNSCC. Our results suggest that adjuvant PD1 inhibitors deserve evaluation in HNSCC patients in whom PD-L1(+) CTCs are detected at the end of curative treatment.
      PubDate: 2017-07-04
       
  • The potential use of lncRNAs found in the 8q24 region as biomarkers for
           colon cancer
    • Authors: White NM; Maher CA.
      Abstract: Colorectal cancer (CRC) is the most common gastrointestinal malignancy in the United States with colon cancer being the fourth most common cause of cancer-related deaths worldwide [1]. However, the incidents of CRC are stabilizing and decreasing in the United States potentially due to increased use of colorectal endoscopy [2]. When localized disease is detected early the 5-year survival rate is 90%. However, survival rates decrease dramatically to only 11% for patients with distant metastasis [3]. Colon cancer is a molecularly heterogeneous disease histologically classified according to tumor-node-metastasis (TNM) to inform treatment options [1]. The risk factors that contribute to colon cancer include age, gender, and familial heritability. Beyond heritability risk factor, the microsatellite instability (MSI) phenotype is found in 15% of colon cancer patients [4]. MSI is a hypermutable phenotype from loss of DNA mismatch repair which is indicative of patient response to therapy and prognosis [1, 4]. But for the majority of colon cancers there is no single genetic ‘driver’ yet known to better identify aggressive disease. However, the dramatic decline in survival rates highlights a clear need to stratify patients for earlier detection and improved targeted treatment options.
      PubDate: 2017-07-03
       
  • CCAT1 and CCAT2 long noncoding RNAs, located within the 8q.24.21 ‘gene
           desert’, serve as important prognostic biomarkers in colorectal cancer
    • Authors: Ozawa TT; Matsuyama TT, Toiyama YY, et al.
      Abstract: AbstractBackground8q24.21 is a frequently amplified genomic region in colorectal cancer (CRC). This region is often referred to as a ‘gene desert’ due to lack of any important protein-coding genes, highlighting the potential role of noncoding RNAs, including long noncoding RNAs (lncRNAs) located around the proto-oncogene MYC. In this study, we have firstly evaluated the clinical significance of altered expression of lncRNAs mapped to this genomic locus in CRC.Patients and methodsA total of 300 tissues, including 280 CRC and 20 adjacent normal mucosa specimens were evaluated for the expression of 12 lncRNAs using qRT-PCR assays. We analyzed the associations between lncRNA expression and various clinicopathological features, as well as with recurrence free survival (RFS) and overall survival (OS) in two independent cohorts.ResultsThe expression of CCAT1, CCAT1-L, CCAT2, PVT1, and CASC19 were elevated in cancer tissues (P = 0.039, <0.001, 0.018, <0.001, 0.002, respectively). Among these, high expression of CCAT1 and CCAT2 was significantly associated with poor RFS (P = 0.049 and 0.022, respectively) and OS (P = 0.028 and 0.015, respectively). These results were validated in an independent patient cohort, in which combined expression of CCAT1 and CCAT2 expression was significantly associated with a poor RFS (HR:2.60, 95% confidence interval [CI]: 1.04–6.06, P = 0.042) and a poor OS (HR:8.38, 95%CI: 2.68–37.0, P < 0.001). We established a RFS prediction model which revealed that combined expression of CCAT1, CCAT2, and carcinoembryonic antigen was a significant determinant for efficiently predicting RFS in stage II (P = 0.034) and stage III (P = 0.001) CRC patients.ConclusionsSeveral lncRNAs located in 8q24.21 locus are highly over-expressed in CRC. High expression of CCAT1 and CCAT2 significantly associates with poor RFS and OS. The expression of these two lncRNAs independently, or in combination, serves as important prognostic biomarkers in CRC.
      PubDate: 2017-06-30
       
  • Prediction of local and metastatic recurrence in solitary fibrous tumor:
           construction of a risk calculator in a multicenter cohort from the French
           Sarcoma Group (FSG) database
    • Authors: Salas SS; Resseguier NN, Blay JY, et al.
      Abstract: AbstractBackgroundSolitary fibrous tumors (SFT) are rare unusual ubiquitous soft tissue tumors that are presumed to be of fibroblastic differentiation. At present, the challenge is to establish accurate prognostic factors. Patients and methodsA total of 214 consecutive patients with SFT diagnosed in 24 participating cancer centers were entered into the European database (www.conticabase.org) to perform univariate and multivariate analysis for overall survival (OS), local recurrence incidence (LRI) and metastatic recurrence incidence (MRI) by taking competing risks into account. A prognostic model was constructed for LRI and MRI. Internal and external validations of the prognostic models were carried out. An individual risk calculator was carried out to quantify the risk of both local and metastatic recurrence.ResultsWe restricted our analysis to 162 patients with local disease. Twenty patients (12.3%) were deceased at the time of analysis and the median OS was not reached. The LRI rates at 10 and 20 years were 19.2% and 38.6%, respectively. The MRI rates at 10 and 20 years were 31.4% and 49.8%, respectively. Multivariate analysis retained age and mitotic count tended to significance for predicting OS. The factors influencing LRI were viscera localization, radiotherapy and age. Mitotic count, tumor localization other than limb and age had independent values for MRI. Three prognostic groups for OS were defined based on the number of unfavorable prognostic factors and calculations were carried out to predict the risk of local and metastatic recurrence for individual patients.ConclusionLRI and MRI rates increased between 10 and 20 years so relapses were delayed, suggesting that long-term monitoring is useful. This study also shows that different prognostic SFT sub-groups could benefit from different therapeutic strategies and that use of a survival calculator could become standard practice in SFTs to individualize treatment based on the clinical situation.
      PubDate: 2017-06-30
       
  • De-escalating and escalating treatments for early-stage breast cancer: the
           St. Gallen International Expert Consensus Conference on the Primary
           Therapy of Early Breast Cancer 2017
    • Authors: Curigliano GG; Burstein HJ, P. Winer EE, et al.
      Abstract: AbstractThe 15th St. Gallen International Breast Cancer Conference 2017 in Vienna, Austria reviewed substantial new evidence on loco-regional and systemic therapies for early breast cancer. Treatments were assessed in light of their intensity, duration and side-effects, seeking where appropriate to escalate or de-escalate therapies based on likely benefits as predicted by tumor stage and tumor biology. The Panel favored several interventions that may reduce surgical morbidity, including acceptance of 2 mm margins for DCIS, the resection of residual cancer (but not baseline extent of cancer) in women undergoing neoadjuvant therapy, acceptance of sentinel node biopsy following neoadjuvant treatment of many patients, and the preference for neoadjuvant therapy in HER2 positive and triple-negative, stage II and III breast cancer. The Panel favored escalating radiation therapy with regional nodal irradiation in high-risk patients, while encouraging omission of boost in low-risk patients. The Panel endorsed gene expression signatures that permit avoidance of chemotherapy in many patients with ER positive breast cancer. For women with higher risk tumors, the Panel escalated recommendations for adjuvant endocrine treatment to include ovarian suppression in premenopausal women, and extended therapy for postmenopausal women. However, low-risk patients can avoid these treatments. Finally, the Panel recommended bisphosphonate use in postmenopausal women to prevent breast cancer recurrence. The Panel recognized that recommendations are not intended for all patients, but rather to address the clinical needs of the majority of common presentations. Individualization of adjuvant therapy means adjusting to the tumor characteristics, patient comorbidities and preferences, and managing constraints of treatment cost and access that may affect care in both the developed and developing world.
      PubDate: 2017-06-21
       
  • Is complete response the answer'
    • Authors: Pusztai LL; Szekely BB, Hatzis CC.
      Abstract: Overall, breast cancer mortality rates decreased by 36% from 1989 to 2012 in the United States, and similar trends have been observed in Europe [1, 2]. The improved survival is attributed to more effective systemic adjuvant therapies and, to a lesser extent, to earlier detection through mammographic screening. Yet, close to 40 000 patients experience metastatic recurrence after an initial diagnosis of stage I–III breast cancer in the United States each year, and therefore the question remains how to further improve the efficacy of adjuvant treatment. Administration of chemotherapy before surgery provides an opportunity to directly assess the cytotoxic activity of a new regimen on the primary tumor and compare it with a standard of care treatment. Not surprisingly, complete eradication of all invasive cancer from the breast and lymph nodes [i.e. pathologic complete response (pCR), ypT0/Tis, ypN0] is associated with an excellent survival at the patient level. Patients with pCR have around a 5% risk of distant metastatic recurrence in 5 years [3]. More extensive residual cancer (RD) is associated with increasingly worse survival in all breast cancer subtypes, but the strongest association is seen in triple negative cancers [3]. This is consistent with the hypothesis that the chemotherapy sensitivity of the distant micrometastases is broadly similar to that of the primary tumor. Indeed, generations of adjuvant chemotherapy regimens that were shown to improve survival also demonstrated increased pCR rates when administered as neoadjuvant therapy compared with earlier regimens (pCRACx4 < pCRAC+taxane < pCRAC+taxane+trastuzumab < pCRAC+taxane+trastuzumab+pertuzumab).
      PubDate: 2017-06-19
       
  • TRAC(ERx)-ing lung cancer evolution
    • Authors: Devarakonda SS; Govindan RR.
      Abstract: Because cancer cells constantly accrue a variety of genetic alterations, subclones arising from founder clones show heterogeneity in their genetic makeup. Cancer cells are exposed to a variety of selection pressures induced by decreased blood supply, hypoxia, and treatment-related effects. This leads to the selection and expansion of subclones with genetic makeup that is ideal for continued survival. Studying the evolution of cancer through multi-regional sampling of tumors and next-generation sequencing technologies can greatly advance our understanding of the selection pressures that operate in cancer, and the molecular mechanisms through which cancers adapt to them. This information has the potential to improve outcomes in the clinic.
      PubDate: 2017-06-19
       
  • Precision, complexity and stigma in advanced prostate cancer terminology:
           it is time to move away from ‘castration-resistant’ prostate cancer
    • Authors: Pezaro CJ; Omlin AA, Mastris KK, et al.
      Abstract: The treatment of men with advanced prostate cancer (APC) is changing rapidly, with several new therapeutic options leading to longer survival. Categorizing clinical states that reflect the cancer biology and prior therapy in men with APC has become more complex. The Prostate Cancer Clinical Trials Working Group (PCWG) developed guidelines that harmonized inclusion, monitoring and outcome definitions for clinical trials in APC [1–3]. PCWG2 guidelines were seminal in changing the terminology from ‘hormone-refractory’ or ‘androgen-independent’ to ‘castration-resistant prostate cancer (CRPC)’, based on evidence of men responding to further hormonal manipulations after primary androgen deprivation therapy (ADT). Both of the approved next-generation endocrine agents, abiraterone acetate and enzalutamide, have shown an overall survival benefit for men with progressive cancer despite castrate levels of testosterone [4, 5]. Thus, adopting the term ‘castration-resistant’ improved the biological accuracy of disease characterization compared with ‘hormone refractory’. The term CRPC, although not unanimously accepted, has become embedded in research and clinical practice.
      PubDate: 2017-06-16
       
  • Surgery for patients with ‘lower grade’ glioma: putting assumptions,
           beliefs and convictions into perspective
    • Authors: Welle MM.
      Abstract: For decades neuro-oncology meetings have benefited from controversial, sometimes heated and emotional debates on the role of surgery for what has traditionally been falsely designated ‘low grade’ glioma; falsely since ‘low grade’ glioma evokes false expectations for often young patients and their caregivers confronted with a disease with a median survival around 7–8 years.
      PubDate: 2017-06-16
       
  • Diffuse pseudoprogression in a patient with metastatic non-small-cell lung
           cancer treated with Nivolumab
    • Authors: Curioni-Fontecedro AA; Ickenberg CC, Franzen DD, et al.
      Abstract: A 72-year-old woman was diagnosed with metastatic non-small-cell lung cancer (NSCLC) stage IV in February 2016. The molecular analysis showed EGFRwt, KRASwt, BRAFwt, ERBB2wt and no translocation or amplification of ALK, ROS1, MET or RET. The patient was treated with Carboplatin and Pemetrexed between February and June 2016 with initial partial response. The following Pemetrexed maintenance therapy was interrupted in September 2016 due to worsening of renal function and disease progression. A second line treatment with Nivolumab (given every two weeks at 3 mg/kg) was started in October 2016. Metastases to adrenal glands and bilateral to the lungs are seen in the PET-CT scan taken at the start of Nivolumab treatment (Figure 1A). Despite development of moderate diarrhea (grade 2), her general condition improved. A PET-CT scan after 6 cycles of Nivolumab showed a morphologic and metabolic response of all lung and adrenal metastases, but an enlargement of several lymph nodes (retroclavicular, mediastinal and at both hili of the lungs) with intense FDG uptake. Moreover, a strong and diffuse FDG-activity was shown pleural, in the right lower lobe, in several bones and in the gut (Figure 1B).
      PubDate: 2017-06-15
       
  • Quality of life predicts overall survival in women with platinum-resistant
           ovarian cancer: an AURELIA substudy
    • Authors: Roncolato FT; Gibbs EE, Lee CK, et al.
      Abstract: AbstractBackgroundWomen with platinum-resistant ovarian cancer are a heterogeneous group whose median overall survival is 12 months. We hypothesized that their quality of life (QoL) scores would be prognostic.Patients and methodsData from AURELIA (n = 326), a randomized trial of chemotherapy with or without bevacizumab, were used to identify baseline QoL domains [EORTC (European Organisation for Research and Treatment of Cancer) QLQ-C30 and OV28] that were significantly associated with overall survival in multivariable Cox regression analyses. Patients were classified as having good, medium, or poor risk. Cutpoints were validated in an independent dataset, CARTAXHY (n = 136). Multivariable analyses of significant QoL domains on survival were adjusted for clinicopathological prognostic factors. The additional QoL information was assessed using C statistic.ResultsIn AURELIA, all domains, except cognitive function, predicted overall survival in univariable analyses. Physical function (P < 0.001) and abdominal/gastrointestinal symptom (P < 0.001) scores remained significant in multivariable models. In high (score <67), medium (67–93), and low (>93) risk categories for physical function, median overall survival was 11.0, 14.7, and 19.3 months, respectively (P < 0.001). In CARTAXHY, median overall survival was 7.9, 16.2, and 23.9 months (P < 0.001), respectively. For high- (>44), medium- (13–44), and low- (<13) risk categories for abdominal/gastrointestinal symptoms, median overall survival was 11.9, 14.3, and 19.7 months in AURELIA (P < 0.001) and 10.5, 19.6, and 24.1 months in CARTAXHY (P = 0.02). Physical function (P = 0.02) and abdominal/gastrointestinal symptoms (P = 0.03) remained independent prognostic factors after adjustment for clinicopathological factors. The C statistic of the full model was 0.71. For QoL factors alone, patient factors alone and disease factors alone, the C statistics were 0.61, 0.61, and 0.67 respectively.ConclusionsPhysical function and abdominal/gastrointestinal symptom scores improved predictions of overall survival over clinicopathological factors alone in platinum-resistant ovarian cancer. This additional prognostic information could improve trial stratification, patient–doctor communication about prognosis, and clinical decision-making.Clinical trial registrationNCT00976911.
      PubDate: 2017-06-08
       
  • Changes in serum interleukin-8 (IL-8) levels reflect and predict response
           to anti-PD-1 treatment in melanoma and non-small-cell lung cancer patients
           
    • Authors: Sanmamed MF; Perez-Gracia JL, Schalper KA, et al.
      Abstract: AbstractBackgroundSurrogate biomarkers of efficacy are needed for anti-PD1/PD-L1 therapy, given the existence of delayed responses and pseudo-progressions. We evaluated changes in serum IL-8 levels as a biomarker of response to anti-PD-1 blockade in melanoma and non-small-cell lung cancer (NSCLC) patients.Patients and methodsMetastatic melanoma and NSCLC patients treated with nivolumab or pembrolizumab alone or nivolumab plus ipilimumab were studied. Serum was collected at baseline; at 2–4 weeks after the first dose; and at the time-points of response evaluation. Serum IL-8 levels were determined by sandwich ELISA. Changes in serum IL-8 levels were compared with the Wilcoxon test and their strength of association with response was assessed with the Mann–Whitney test. Accuracy of changes in IL-8 levels to predict response was estimated using receiver operation characteristics curves.ResultsTwenty-nine melanoma patients treated with nivolumab or pembrolizumab were studied. In responding patients, serum IL-8 levels significantly decreased between baseline and best response (P <0.001), and significantly increased upon progression (P =  0.004). In non-responders, IL-8 levels significantly increased between baseline and progression (P =  0.013). Early changes in serum IL-8 levels (2–4 weeks after treatment initiation) were strongly associated with response (P <0.001). These observations were validated in 19 NSCLC patients treated with nivolumab or pembrolizumab (P =  0.001), and in 15 melanoma patients treated with nivolumab plus ipilimumab (P <0.001). Early decreases in serum IL-8 levels were associated with longer overall survival in melanoma (P =  0.001) and NSCLC (P =  0.015) patients. Serum IL-8 levels also correctly reflected true response in three cancer patients presenting pseudoprogression.ConclusionsChanges in serum IL-8 levels could be used to monitor and predict clinical benefit from immune checkpoint blockade in melanoma and NSCLC patients.
      PubDate: 2017-06-08
       
  • Gonadotropin-releasing hormone analogs for ovarian function protection
           during chemotherapy in young early breast cancer patients: the last piece
           of the puzzle'
    • Authors: Del Mastro LL; Lambertini MM.
      Abstract: In western countries, nearly 6% of women with newly diagnosed breast cancer are younger than 40 years old [1]. This percentage rises to 25% in developing countries [2]. At least half of young women with breast cancer desire children after treatment [3]. Nevertheless, breast cancer patients have the lowest chances among cancer survivors to subsequently become pregnant [4]. A potential important cause of such a low pregnancy rate in breast cancer survivors is represented by the possible gonadal damage induced by anticancer systemic therapies [5]. At the time of treatment decision-making, ∼50% of young breast cancer patients are concerned about the potential risk of developing chemotherapy-induced premature ovarian failure (POF) and subsequent fertility impairment [6]. Embryo or oocyte cryopreservation is considered standard fertility preserving techniques but they cannot protect gonadal function during chemotherapy [4, 7]. Temporary ovarian suppression with gonadotropin-releasing hormone analogs (GnRHa) during chemotherapy is another available option that has been mainly investigated as a strategy to preserve ovarian function during systemic cytotoxic therapy [5]. However, this strategy has been widely debated in the last years with supporters [8] and strong detractors [9] of its protective role.
      PubDate: 2017-05-29
       
  • Refining prognosis in early-stage colorectal cancer: one or multiple genes
           at a time'
    • Authors: Willis JA; Vilar EE.
      Abstract: Based on recent estimates, colon cancer remains the third most common newly diagnosed cancer type among both men and women in the United States [1]. At the time of curative surgical resection, stage II (node-negative) and stage III (node-positive) account for approximately 25% and 35% of new cases, respectively [2]. However, while multiple lines of evidence support the benefit of adjuvant systemic therapy in stage III disease, its exact role in stage II disease continues to be the subject of lively debate and active investigation [3].
      PubDate: 2017-05-26
       
  • Whose side are you on'
    • Authors: Taieb JJ.
      Abstract: Data on the prognostic and predictive values of primary tumor sidedness in metastatic colorectal cancer (mCRC) patients have, over the last year or so, been reported at oncology meetings and, in some cases, published subsequently as full articles. The present edition of Annals of Oncology includes two major articles, one on the impact of tumor sidedness in three panitumumab trials [1] and the other a meta-analysis of published and unpublished data from randomized controlled trials, comparing chemotherapy plus anti-epidermal growth factor receptors (EGFRs) with chemotherapy alone or combined with bevacizumab [2]. The vast majority of these trials deal with treatment-naive RAS wild-type mCRC patients, except for one in the meta-analysis which is testing chemotherapy plus or minus panitumumab in a second-line setting.
      PubDate: 2017-05-25
       
  • Does chemoselection open the door for immunotherapy'
    • Authors: Jacobs MT; Ruiz AL, Cohen EE.
      Abstract: The TISOC-1 trial addresses the important question of utilizing chemoselection with response to induction chemotherapy to stratify patients into early or late surgical resection of tumors [1]. This study raises several interesting ideas on how to tackle the challenges of treating cancer patients in an age where we are seeing an evolution of treatments available ranging from traditional chemoradiation to immunotherapy and targeted small-molecule inhibitors. Using a chemoselection approach, we have the potential to create tailored treatments for patients avoiding unnecessary toxicities. Several important questions emerge from the TISCO-1 trial, including (i) can induction chemotherapy be used to optimize current treatment options' (ii) in patients who respond to induction therapy can organ preserving surgery, avoiding radical neck dissections, be employed' and (iii) do induction chemotherapy nonresponders benefit from immunotherapy'
      PubDate: 2017-05-25
       
  • Everolimus with paclitaxel and carboplatin as first-line treatment for
           metastatic large-cell neuroendocrine lung carcinoma: a multicenter phase
           II trial
    • Authors: Christopoulos PP; Engel-Riedel WW, Grohé CC, et al.
      Abstract: AbstractBackgroundLarge-cell neuroendocrine carcinoma of the lung (LCNEC) is a rare disease with poor prognosis and limited treatment options. Neuroendocrine tumors frequently show overactivation of the mTOR pathway. Based on the good activity of the mTOR inhibitor everolimus in different types of neuroendocrine tumors and the results of a previous phase I trial, we evaluated the efficacy and safety of everolimus in combination with carboplatin and paclitaxel as upfront treatment for patients with advanced LCNEC.Patients and methodsIn this prospective, multicenter phase II trial chemotherapy-naive patients with stage IV LCNEC received 5 mg everolimus daily combined with paclitaxel 175 mg/m2 and carboplatin AUC 5 every 3 weeks for a maximum of four cycles followed by maintenance everolimus 5 mg daily until progression. Efficacy parameters were determined based on central radiologic assessment.ResultsForty-nine patients with a mean age of 62 ±9 years and a predominance of male (71%) smokers (98%) were enrolled in 10 German centers. The overall response rate was 45% (95% confidence interval [CI] 31%–60%), the disease control rate 74% (CI 59%–85%), the median progression-free survival 4.4 (CI 3.2–6) months and the median overall survival 9.9 (CI 6.9–11.7) months. The progression-free survival rate at 3 months (primary end point) was 76% (CI 64%–88%) according to Kaplan–Meier. Grade-3/4 toxicities occurred in 51% of patients and mainly consisted of general physical health deterioration (8%), cytopenias (24%), infections (10%) and gastrointestinal problems (8%). Typical everolimus-related adverse events, like stomatitis, rash and ocular problems occurred only in a minority of patients (<15%) and were exclusively of grade 1–2.ConclusionEverolimus in combination with carboplatin and paclitaxel is an effective and well-tolerated first-line treatment for patients with metastatic LCNEC.Registered clinical trial numbersEudraCT number 2010-022273-34, NCT01317615.
      PubDate: 2017-05-23
       
  • Discovery and development of novel therapies in advanced breast cancer:
           rapid development of ribociclib
    • Authors: Germa CC; Miller MM, Mukhopadhyay PP, et al.
      PubDate: 2017-05-19
       
  • Lymphocyte density determined by computational pathology validated as a
           predictor of response to neoadjuvant chemotherapy in breast cancer:
           secondary analysis of the ARTemis trial
    • Authors: Ali HR; Dariush AA, Thomas JJ, et al.
      Abstract: AbstractBackgroundWe have previously shown lymphocyte density, measured using computational pathology, is associated with pathological complete response (pCR) in breast cancer. The clinical validity of this finding in independent studies, among patients receiving different chemotherapy, is unknown.Patients and methodsThe ARTemis trial randomly assigned 800 women with early stage breast cancer between May 2009 and January 2013 to three cycles of docetaxel, followed by three cycles of fluorouracil, epirubicin and cyclophosphamide once every 21 days with or without four cycles of bevacizumab. The primary endpoint was pCR (absence of invasive cancer in the breast and lymph nodes). We quantified lymphocyte density within haematoxylin and eosin (H&E) whole slide images using our previously described computational pathology approach: for every detected lymphocyte the average distance to the nearest 50 lymphocytes was calculated and the density derived from this statistic. We analyzed both pre-treatment biopsies and post-treatment surgical samples of the tumour bed.ResultsOf the 781 patients originally included in the primary endpoint analysis of the trial, 609 (78%) were included for baseline lymphocyte density analyses and a subset of 383 (49% of 781) for analyses of change in lymphocyte density. The main reason for loss of patients was the availability of digitized whole slide images. Pre-treatment lymphocyte density modelled as a continuous variable was associated with pCR on univariate analysis (odds ratio [OR], 2.92; 95% CI, 1.78–4.85; P < 0.001) and after adjustment for clinical covariates (OR, 2.13; 95% CI, 1.24–3.67; P = 0.006). Increased pre- to post-treatment lymphocyte density showed an independent inverse association with pCR (adjusted OR, 0.1; 95% CI, 0.033–0.31; P < 0.001).ConclusionsLymphocyte density in pre-treatment biopsies was validated as an independent predictor of pCR in breast cancer. Computational pathology is emerging as a viable and objective means of identifying predictive biomarkers for cancer patients.ClinicalTrials.govNCT01093235.
      PubDate: 2017-05-19
       
  • First-onset mental disorders after cancer diagnosis and cancer-specific
           mortality: a nationwide cohort study
    • Authors: Zhu JJ; Fang FF, Sjölander AA, et al.
      Abstract: AbstractBackgroundThe diagnosis of cancer is strongly associated with the risk of mental disorders even in patients with no previous history of mental disorders. Accumulating data suggest that mental distress may accelerate tumor progression. We hypothesized therefore that mental disorders after a cancer diagnosis may increase the risk of cancer-specific mortality.Patients and methods We conducted a nationwide cohort study including 244 261 cancer patients diagnosed in Sweden during 2004–2009 and followed them through 2010. Through the Swedish Patient Register, we obtained clinical diagnoses of all mental disorders and focused on mood-, anxiety-, and substance abuse disorders (ICD10: F10–F16, F18–F19, F32–F33, F40–F41, and F43–45) that are commonly diagnosed among patients with cancer. We further classified the studied mental disorders into first-onset or recurrent mental disorders. We used Cox regression to estimate multivariable hazard ratios (HRs) with 95% confidence intervals (CIs) as a measure of the association between mental disorders after cancer diagnosis and cancer-specific mortality, adjusting for age, sex, calendar period, educational level, cancer stage, and cancer type at diagnosis.ResultsAfter cancer diagnosis, 11 457 patients were diagnosed with mood-, anxiety-, and substance abuse disorders; of which 7236 were first-onset mental disorders. Patients with a first-onset mental disorder were at increased risk of cancer-specific mortality (HR: 1.82, 95% CI: 1.71–1.92) while patients with a recurrent mental disorder had much lower risk elevation (HR: 1.14, 95% CI: 1.05–1.24). The increased cancer-specific mortality by first-onset mental disorders was observed for almost all cancer sites/groups and the association was stronger for localized cancers (HR: 2.00, 95% CI: 1.73–2.31) than for advanced cancers (HR: 1.49, 95% CI: 1.32–1.69).ConclusionsPatients with a first-onset common mood-, anxiety-, or substance abuse disorder after cancer diagnosis may be at increased risk of cancer-specific death.
      PubDate: 2017-05-19
       
  • Beta blockers and improved progression-free survival in patients with
           advanced HER2 negative breast cancer: a retrospective analysis of the
           ROSE/TRIO-012 study
    • Authors: Spera GG; Fresco RR, Fung HH, et al.
      Abstract: AbstractBackgroundRecent retrospective studies suggest that beta-adrenergic blocking drugs (BB) are associated with improved outcomes in patients with a range of cancers. Although limited and discordant data suggest that BB may increase overall survival (OS) in localized breast cancer (BC), there is no information on the effects of BB in women with advanced BC.Patients and methodsTo explore the association between BB use and BC outcomes, we retrospectively reviewed ROSE/TRIO-012, a double-blinded, multinational phase III trial that randomized 1144 patients with HER2-negative advanced BC to first-line docetaxel in combination with ramucirumab or placebo. We compared progression-free survival (PFS), OS, overall response rate, and clinical benefit rate in patients who received BB to those who did not.Results153/1144 (13%) patients received BB; 62% prior to enrolment and 38% began after enrolment. Median PFS in BB treated patients was longer than in patients who did not receive them (10.3 versus 8.3 months; HR 0.81; 95% CI 0.66–0.99; P = 0.038). Patients treated with BB only after enrolment had even higher median PFS (15.5 versus 8.3 months, P < 0.001). In the TNBC subset, median PFS was 13.0 months with BB, compared to 5.2 months without BB (HR 0.52; 95% CI 0.34–0.79; P = 0.002). The benefit of BB intake in PFS was independent of treatment-emergent hypertension (P = 0.476) but associated with treatment arm (P = 0.037). The test for interactions between BB and treatment arm was not significant (P = 0.276). No differences were seen in OS, overall response rate, or clinical benefit rate. A validation dataset analysis had consistent but less substantial improved outcomes for women with node positive operable breast cancer receiving BB in the BCIRG-005 trial.ConclusionsIn this exploratory analysis, BB intake was associated with significant improvement in PFS, particularly in patients with TNBC and patients not previously exposed to BB.Clinical trial numberNCT00703326.
      PubDate: 2017-05-18
       
  • Assessment of nivolumab benefit–risk profile of a 240-mg flat dose
           relative to a 3-mg/kg dosing regimen in patients with advanced tumors
    • Authors: Zhao XX; Suryawanshi SS, Hruska MM, et al.
      Abstract: AbstractBackgroundNivolumab 3 mg/kg every 2 weeks (Q2W) has shown benefit versus the standard of care in melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). However, flat dosing is expected to shorten preparation time and improve ease of administration. With knowledge of nivolumab safety, efficacy, and pharmacokinetics across a wide dose range in body weight (BW) dosing, assessment of the benefit–risk profile of a 240-mg flat dose relative to the approved 3-mg/kg dose was approached by quantitative clinical pharmacology.Patients and methodsA flat dose of 240 mg was selected based on its equivalence to the 3-mg/kg dose at the median BW of ∼80 kg in patients in the nivolumab program. The benefit–risk profile of nivolumab 240 mg was evaluated by comparing exposures at 3 mg/kg Q2W and 240 mg Q2W across BW and tumor types; clinical safety at 3 mg/kg Q2W by BW and exposure quartiles in melanoma, NSCLC, and RCC; and safety and efficacy at 240 mg Q2W relative to 3 mg/kg Q2W in melanoma, NSCLC, and RCC.ResultsThe median nivolumab exposure and its distribution at 240 mg Q2W were similar to 3 mg/kg Q2W in the simulated population. Safety analyses did not demonstrate a clinically meaningful relationship between BW or nivolumab exposure quartiles and frequency or severity of adverse events. The predicted safety and efficacy were similar across nivolumab exposure ranges achieved with 3 mg/kg Q2W or 240 mg Q2W flat dose.ConclusionBased on population pharmacokinetic modeling, established flat exposure–response relationships for efficacy and safety, and clinical safety, the benefit–risk profile of nivolumab 240 mg Q2W was comparable to 3 mg/kg Q2W. The quantitative clinical pharmacology approach provided evidence for regulatory decision-making on dose modification, obviating the need for an independent clinical study.
      PubDate: 2017-05-17
       
  • Salvage high-dose chemotherapy in female patients with relapsed/refractory
           germ-cell tumors: a retrospective analysis of the European Group for Blood
           and Marrow Transplantation (EBMT)
    • Authors: De Giorgi UU; Richard SS, Badoglio MM, et al.
      Abstract: AbstractBackgroundHigh-dose chemotherapy (HDC) with hematopoietic progenitor cell transplantation is a standard option for relapsed/refractory testicular germ-cell tumor (GCT), but only few data have been reported in female patients with GCT. We conducted a retrospective analysis of female patients with GCT treated with HDC and registered with the European Society for Blood and Marrow Transplantation.Patients and methodsBetween 1985 and 2013, 60 registered female patients with GCT, median age 27 years (range 15–48), were treated with salvage HDC. Forty patients (67%) had primary ovarian GCT, 8 (13%) mediastinal, 7 (12%) retroperitoneal and 5 (8%) other primary sites/unknown. Twenty-two patients (37%) received HDC as second-line therapy, 29 (48%) as third-line, and 9 (15%) as fourth- to sixth-line. Nine of 60 patients (15%) received HDC as late-intensification with no evidence of metastasis before HDC. The conditioning HDC regimens comprised carboplatin in 51 of 60 cases (85%), and consisted of a single HDC cycle in 31 cases (52%), a multi-cycle HDC regimen in 29 (48%).Results Nine cases who underwent late intensification HDC were not evaluable for response. Of the other 51 assessable patients, 17 (33%) achieved a complete response (CR), 8 (16%) a marker-negative partial remission (PRm−), 5 (10%) a marker-positive partial remission, 5 (10%) stable disease, and 13 (25%) progressive disease. There were 3 toxic deaths (6%). With an overall median follow-up of 14 months (range 1–219), 7 of 9 (78%) patients with late intensification and 18 of the 25 patients (72%) achieving a CR/PRm− following HDC were free of relapse/progression. In total, 25 of 60 patients (42%) were progression-free following HDC at a median follow-up of 87 months (range 3–219 months).ConclusionsSalvage HDC based on carboplatin represents a therapeutic option for female patients with relapsed/refractory GCT.
      PubDate: 2017-05-16
       
  • 64 Cu-DOTA-trastuzumab PET imaging for HER2-specific primary lesions of
           breast cancer
    • Authors: Sasada SS; Kurihara HH, Kinoshita TT, et al.
      Abstract: The treatment strategy for breast cancer is determined based on hormonal receptors and human epidermal growth factor receptor 2 (HER2) status. HER2 expression may change during the course of the disease [1]. HER2 expression status is routinely assessed using tumor tissue obtained invasively by either biopsy or operation, and tissue from a tumor lesion may be difficult to obtain, especially in the recurrent or metastatic setting. Radiographic examination, which could non-invasively determine HER2 status, would be beneficial in such circumstances. Previous reports showed that 64Cu-DOTA-trastuzumab positron emission tomography (HER2-PET) imaging could be used to visualize primary and metastatic HER2-positive lesions [2–4]. We have conducted a present study to evaluate the concordance of HER2 expression status of primary breast tumors between HER2-PET imaging and immunohistochemistry (IHC). The selective criteria were listed at UMIN000017446, and PET/CT scans were carried out 48 h after 64Cu-DOTA-trastuzumab injection, as described previously [2].
      PubDate: 2017-05-15
       
  • A two-arm multicenter phase II trial of one cycle chemoselection
           split-dose docetaxel, cisplatin and 5-fluorouracil (TPF) induction
           chemotherapy before two cycles of split TPF followed by curative surgery
           combined with postoperative radiotherapy in patients with locally advanced
           oral and oropharyngeal squamous cell cancer (TISOC-1)
    • Authors: Inhestern JJ; Schmalenberg HH, Dietz AA, et al.
      Abstract: AbstractBackgroundInduction chemotherapy (ICT) with docetaxel, cisplatin and fluorouracil (TPF) followed by radiotherapy is an effective treatment option for locally advanced head and neck cancer. This phase II study investigated the effectivity of a split-dose TPF ICT before surgery for locally advanced resectable (stage III/IVA) oral and oropharyngeal cancer.Patients and methodsPatients received TPF split on two dosages on days 1 and 8 per cycle (30 mg/m2 docetaxel, 40 mg/m2 cisplatin, 2000 mg/m2 fluorouracil per week). Responders (reduction tumor volume ≥30% after first cycle) received three 3-week cycles and non-responders only one cycle before surgery and postoperative radio(chemo)therapy (RCT). The primary endpoint was progression-free survival rate after 24 months. Secondary endpoints were amongst others overall survival, histopathological response to ICT, toxicity, quality of life and swallowing function.ResultsFifty-four patients (91% stage IVA, 87% male, 72% oropharyngeal cancer, 70% responders) were eligible for a per-protocol analysis. The progression-free survival rate after 24 months was 88.5% for responders and 60.6% for non-responders (P = 0.005). The overall survival rate after 24 months was 97.3% for responders and 73.7% for non-responders (P = 0.032). The rate of histopathological complete remission of the primary tumor was higher in responders (P = 0.015). High-risk classification for postoperative RCT was lower in responders (P < 0.0001). The most common grade 3+ adverse event was neutropenia in 26% of patients during ICT and mucositis in 13% during postoperative RCT. During treatment and follow-up quality of life and swallowing function was not different between responders and non-responders.ConclusionPatients with oral and oropharyngeal cancer responding to split-dose TPF before surgery and postoperative RCT show good oncological results. The tri-modal treatment regime was well tolerated. ICT using tumor response as criterion for duration of ICT before surgery of oral and oropharyngeal cancer merits additional investigation in a phase III study.Clinical trial numberNCT01108042.
      PubDate: 2017-05-11
       
  • Early results of a randomized two-by-two factorial phase II trial
           comparing neoadjuvant chemotherapy with two and four courses of
           cisplatin/S-1 and docetaxel/cisplatin/S-1 as neoadjuvant chemotherapy for
           locally advanced gastric cancer
    • Authors: Aoyama TT; Nishikawa KK, Fujitani KK, et al.
      Abstract: AbstractBackgroundNeoadjuvant chemotherapy (NAC) is a promising method of improving the survival of resectable gastric cancer. Cisplatin/S-1 (CS) and docetaxel/cisplatin/S-1 (DCS) are both effective against metastatic gastric cancer. This report clarified the impact of these regimens on early endpoints, including the pathological responses, chemotherapy-related toxicities, and surgical results.MethodsPatients with M0 and either T4 or T3 in case of junctional cancer or scirrhous type received two or four courses of cisplatin (60 mg/m2 at day 8)/S-1 (80 mg/m2 for 21 days with 1 week rest) or docetaxel (40 mg/m2 at day 1)/cisplatin (60 mg/m2 at day 1)/S-1 (80 mg/m2 for 14 days with 2 weeks rest) as NAC. Patients then underwent D2 gastrectomy and adjuvant S-1 chemotherapy for 1 year. The primary endpoint was the 3-year overall survival.ResultsBetween October 2011 and September 2014, 132 patients were assigned to receive CS (n = 66; 33 in 2 courses and 33 in 4 courses) or DCS (n = 66; 33 in 2 courses and 33 in 4 courses). The respective major grade 3 or 4 hematological toxicities (CS/DCS) were leukocytopenia (14.1%/26.2%), neutropenia (29.7%/47.7%), anemia (14.1%/12.3%), and platelet reduction (3.1%/1.5%). The rate of pathological response, defined as a complete response or < 10% residual cancer remaining, was 19.4% in the CS group and 15.4% in the DCS group, and 15.6% in the two-course group and 19.0% in the 4-course group. The R0 resection rate was 72.7% in the CS group and 81.8% in the DCS group and 80.3% in the two-course group and the 74.2% in the four-course group. No treatment-related deaths were observed.ConclusionsOur results do not support three-drug therapy with a taxane over two-drug therapy, or any further treatment beyond two cycles as an attractive candidate for the test arm of NAC.
      PubDate: 2017-05-09
       
  • A prospective multicentre phase III validation study of AZGP1 as a
           biomarker in localized prostate cancer
    • Authors: Zhang AY; Grogan JS, Mahon KL, et al.
      Abstract: AbstractBackgroundProstate cancers (PCs) with similar characteristics at the time of diagnosis can have very different disease outcomes. Conventional biomarkers of PC still lack precision in identifying individuals at high risk of PC recurrence. While many candidate biomarkers are proposed in the literature, few are in clinical practice as they lack rigorous validation. This study prospectively enrolled an independent phase III cohort to evaluate the clinical utility of zinc-alpha 2-glycoprotein (AZGP1) as a prognostic biomarker in localized PC.Patients and methodsIn our multicentre, prospective phase III study, AZGP1 status in 347 radical prostatectomy specimens was assayed by immunohistochemistry in a NATA-accredited laboratory. The AZGP1 score was assessed in a multivariable model incorporating established prognostic factors. We also report extended outcomes from our previous phase II study. The primary endpoint was biochemical relapse-free survival (BRFS). Secondary endpoints were metastasis-free survival (MFS) and PC-specific survival (PCSS).ResultsIn the phase II cohort, with a median follow-up of 15.8 years, low/absent AZGP1 expression was an independent predictor of poor BRFS (HR, 1.4; 95% CI, 1.1–1.9; P = 0.03), MFS (HR, 2.8; 95% CI, 1.2–6.6; P = 0.02) and PCSS (HR, 3.8; 95% CI, 1.5–9.5; P = 0.005). These results were validated in our prospective phase III cohort. Low/absent AZGP1 expression independently predicted for BRFS (HR, 1.9; 95% CI, 1.1–3.3; P = 0.02), with shorter MFS (HR, 2.0; 95% CI, 1.1–3.4; P = 0.02). AZGP1 improved the discriminatory value when incorporated into existing prognostic risk models.ConclusionOur study provides prospective phase III validation that absent/low AZGP1 expression provides independent prognostic value in PC. This study provides robust evidence for the incorporation of this biomarker into clinical practice.
      PubDate: 2017-05-09
       
  • Bevacizumab with or after chemotherapy for platinum-resistant recurrent
           ovarian cancer: exploratory analyses of the AURELIA trial
    • Authors: Bamias AA; Gibbs EE, Khoon Lee CC, et al.
      Abstract: AbstractBackgroundIn the open-label randomized phase III AURELIA trial, adding bevacizumab to chemotherapy for platinum-resistant ovarian cancer (PROC) significantly improved progression-free survival and response rate versus chemotherapy alone, but not overall survival (OS). We explored the effect of bevacizumab use after disease progression (PD) in patients randomized to chemotherapy alone.Patients and methodsIn AURELIA, 361 women with PROC were randomized to chemotherapy alone or with bevacizumab. Patients initially randomized to chemotherapy were offered bevacizumab after PD. Post hoc analyses assessed efficacy and safety in three subgroups: chemotherapy alone, chemotherapy followed by bevacizumab after PD, and chemotherapy plus bevacizumab at randomization.ResultsOf the 182 patients randomized to chemotherapy alone, 72 (40%) received bevacizumab after PD and 110 (60%) never received bevacizumab. There were no significant differences in patient and disease characteristics between these subgroups at baseline or the time of PD. Compared with patients never receiving bevacizumab, the risk of death was significantly reduced in patients receiving bevacizumab either upfront with chemotherapy [hazard ratio (HR) = 0.68, 95% confidence interval (CI) 0.52–0.90] or after PD (HR = 0.60, 95% CI 0.43–0.86). The tolerability of bevacizumab was similar with administration upfront or after PD.ConclusionsPost-PD bevacizumab use may have confounded OS results in AURELIA. In these exploratory analyses of non-randomized subgroups, bevacizumab use, either with chemotherapy or after PD on chemotherapy alone, improved OS compared with no bevacizumab. Combining bevacizumab with chemotherapy at first appearance of platinum resistance maximises the likelihood of patients receiving this active treatment for PROC. ClinicalTrials.gov: NCT00976911.
      PubDate: 2017-05-08
       
  • No benefit from the addition of anti-EGFR antibody in all right-sided
           metastatic colorectal cancer'
    • Authors: Sunakawa YY; Tsuji AA, Fujii MM, et al.
      Abstract: Sub-analyses of the CRYSTAL and FIRE-3 trials showed a clear benefit in metastatic colorectal cancer (mCRC) patients with left-sided tumors (L) but limited benefit in patients with right-sided tumors (R) derived from the addition of cetuximab to first-line chemotherapy [1]. Tumor location subgroup data from the CALGB/SWOG 80405 trial were similar to sub-analysis data of the FIRE-3 regarding the prognostic and predictive impact of tumor sidedness [2]. These findings would lead to confirmation that tumor sidedness has prognostic and predictive value in mCRC. According to these consistent results, the updated National Comprehensive Cancer Network guidelines (version 1. 2017) <www.nccn.org/professionals/physician_gls/f_guidelines.asp > indicated a strong statement that anti-Epidermal Growth Factor Receptor (EGFR) antibody should be combined with first-line treatment in only mCRC patients with RAS wild-type and L. All patients with R should avoid receiving anti-EGFR antibodies as an initial therapy in clinical practice'
      PubDate: 2017-05-05
       
  • Surgical resection versus watchful waiting in low-grade gliomas
    • Authors: Jakola AS; Skjulsvik AJ, Myrmel KS, et al.
      Abstract: AbstractBackgroundInfiltrating low-grade gliomas (LGG; WHO grade 2) typically present with seizures in young adults. LGGs grow continuously and usually transform to higher grade of malignancy, eventually causing progressive disability and premature death. The effect of up-front surgery has been controversial and the impact of molecular biology on the effect of surgery is unknown. We now present long-term results of upfront surgical resection compared with watchful waiting in light of recently established molecular markers.Materials and methodsPopulation-based parallel cohorts were followed from two Norwegian university hospitals with different surgical treatment strategies and defined geographical catchment regions. In region A watchful waiting was favored while early resection was favored in region B. Thus, the treatment strategy in individual patients depended on their residential address. The inclusion criteria were histopathological diagnosis of supratentorial LGG from 1998 through 2009 in patients 18 years or older. Follow-up ended 1 January 2016. Making regional comparisons, the primary end-point was overall survival.ResultsA total of 153 patients (66 from region A, 87 from region B) were included. Early resection was carried out in 19 (29%) patients in region A compared with 75 (86%) patients in region B. Overall survival was 5.8 years (95% CI 4.5–7.2) in region A compared with 14.4 years (95% CI 10.4–18.5) in region B (P < 0.01). The effect of surgical strategy remained after adjustment for molecular markers (P = 0.001).ConclusionIn parallel population-based cohorts of LGGs, early surgical resection resulted in a clinical relevant survival benefit. The effect on survival persisted after adjustment for molecular markers.
      PubDate: 2017-05-05
       
  • A double-blind, placebo-controlled randomized trial of creatine for the
           cancer anorexia/weight loss syndrome (N02C4): an Alliance trial
    • Authors: Jatoi AA; Steen PD, Atherton PJ, et al.
      Abstract: AbstractBackgroundMultiple pilot studies, including one in colorectal cancer patients, suggest that creatine, an amino acid derivative, augments muscle, improves strength, and thereby could palliate the cancer anorexia/weight loss syndrome.Patients and methodsIn this randomized, double-blind, placebo-controlled trial, incurable patients with this syndrome were assigned creatine (20 g/day load×5 days followed by 2 g/day orally) versus identical placebo. Patients were weighed once a week for 1 month and then monthly. Patients were also assessed over 1 month for appetite and quality of life (validated questionnaires), fist grip strength, body composition (bioelectrical impedance), and adverse events. The primary endpoint was 10% or greater weight gain from baseline during the first month.ResultsWithin this combined cohort of 263 evaluable patients (134 received creatine and 129 placebo), only 3 gained ≥10% of their baseline weight by 1 month: two creatine-treated and the other placebo-exposed (P = 1.00). Questionnaire data on appetite, quality of life, and activities of daily living showed no statistically significant differences between groups. Similarly, no statistically significant differences between groups were observed for fist-grip strength or body composition. Rates and severity of adverse events were comparable between groups. Finally, a median survival of 230 and 239 days were observed in the creatine and placebo groups, respectively (P = 0.70).ConclusionCreatine, as prescribed in this trial, had no effect on the cancer anorexia/weight loss syndrome.
      PubDate: 2017-05-05
       
  • ROMANA 3: a phase 3 safety extension study of anamorelin in advanced
           non-small-cell lung cancer (NSCLC) patients with cachexia
    • Authors: Currow DD; Temel JS, Abernethy AA, et al.
      Abstract: AbstractBackgroundCancer anorexia–cachexia is a debilitating condition frequently observed in NSCLC patients, characterized by decreased body weight, reduced food intake, and impaired quality of life. Anamorelin, a novel selective ghrelin receptor agonist, has anabolic and appetite-enhancing activities.Patients and methodsROMANA 3 was a safety extension study of two phase 3, double-blind studies that assessed safety and efficacy of anamorelin in advanced NSCLC patients with cachexia. Patients with preserved Eastern Cooperative Oncology Group ≤2 after completing 12 weeks (w) on the ROMANA 1 or ROMANA 2 trials (0–12 weeks) could enroll in ROMANA 3 and continue to receive anamorelin 100 mg or placebo once daily for an additional 12w (12–24 weeks). The primary endpoint of ROMANA 3 was anamorelin safety/tolerability (12–24 weeks). Secondary endpoints included changes in body weight, handgrip strength (HGS), and symptom burden (0–24 weeks).ResultsOf the 703 patients who completed ROMANA 1 and ROMANA 2, 513 patients entered ROMANA 3 (anamorelin, N = 345, mean age 62.0 years; placebo, N = 168; mean age 62.2 years). During ROMANA 3, anamorelin and placebo groups had similar incidences of treatment–emergent adverse events (TEAEs; 52.2% versus 55.7%), grade ≥3 TEAEs (22.4% versus 21.6%), and serious TEAEs (12.8% versus 12.6%). There were 36 (10.5%) and 23 (13.8%) deaths in the anamorelin and placebo groups, respectively; none were drug-related. Improvements in body weight and anorexia–cachexia symptoms observed in the original trials were consistently maintained over 12–24 weeks. Anamorelin, versus placebo, significantly increased body weight from baseline of original trials at all time points (P < 0.0001) and improved anorexia–cachexia symptoms at weeks 3, 6, 9, 12, and 16 (P < 0.05). No significant improvement in HGS was seen in either group.ConclusionDuring the 12–24 weeks ROMANA 3 trial, anamorelin continued to be well tolerated. Over the entire 0–24w treatment period, body weight and symptom burden were improved with anamorelin.Clinical trial registration numbersROMANA 1 (NCT01387269), ROMANA 2 (NCT01387282), and ROMANA 3 (NCT01395914).
      PubDate: 2017-05-04
       
  • Immune checkpoint-associated cardiotoxicity: case report with systematic
           review of literature
    • Authors: Chauhan AA; Burkeen GG, Houranieh JJ, et al.
      Abstract: Immune checkpoint inhibitors have taken the world of oncology by storm. More than 20 candidate drugs are currently being investigated in over 800 registered clinical trials for various malignant processes. Ipilumumab, nivolumab, pembrolizumab, and atezoluzimab have been approved by the United States Food and Drug Administration for melanoma, lung cancer, bladder cancer, renal cancer, and most recently Hodgkin’s lymphoma. This list is increasing and with the rapid and wide use of this novel drug class, new and/or rare side effects are occurring more frequently in clinical practice than initially reported through approval trials. We report one such case of nivolumab-induced cardiotoxicity, which prompted us to perform a literature review.
      PubDate: 2017-05-02
       
  • GnRH agonist for protection against ovarian toxicity during chemotherapy
           for early breast cancer: the Anglo Celtic Group OPTION trial
    • Authors: Leonard RF; Adamson DA, Bertelli GG, et al.
      Abstract: AbstractBackgroundChemotherapy-induced premature ovarian insufficiency (POI) impacts fertility and other aspects of women’s health. The OPTION trial tested whether administration of a gonadotropin-releasing hormone agonist during chemotherapy for early breast cancer reduced the risk of POI.Patients and methodsThis was a prospective, randomized, parallel group study of the gonadotropin-releasing hormone agonist goserelin administered before and during chemotherapy for breast cancer with stage I–IIIB disease. The primary outcome was amenorrhoea between 12 and 24 months after randomization, supported by elevated follicle stimulating hormone concentrations to give an additional analysis as rate of POI.ResultsA total of 227 patients were randomized and the primary analysis was conducted on 202 patients. Goserelin reduced the prevalence of amenorrhoea between 12 and 24 months to 22% versus 38% in the control group (P = 0.015) and the prevalence of POI to 18.5% versus 34.8% in the control group (P = 0.048). Follicle stimulating hormone concentrations were also lower in all women treated with goserelin at both 12 and 24 months (P = 0.027, P = 0.001, respectively). The effect of goserelin was not statistically significant in women >40 years. Assessment of the ovarian reserve using anti-Müllerian hormone showed a marked fall in both groups during treatment to median values of 5% of pretreatment levels in the control group and 7% in the goserelin group, which were not significantly different between groups.ConclusionThis study shows that goserelin reduced the risk of POI in women treated with chemotherapy for early breast cancer, with particular efficacy in women aged ≤40 years old. The degree of ovarian protection also seems limited and the clinical significance for fertility and longer term prevention of estrogen deficiency-related outcomes needs to be determined.
      PubDate: 2017-05-02
       
  • Cost-effectiveness of palbociclib in hormone receptor-positive advanced
           breast cancer
    • Authors: Mamiya HH; Tahara RK, Tolaney SM, et al.
      Abstract: AbstractBackgroundPalbociclib (PAL), a novel small-molecule inhibitor of cyclin-dependent kinases 4 and 6 for the treatment of advanced breast cancer, has demonstrated significant efficacy in prolonging progression-free survival when added to existing therapies. Considering the high cost of PAL, we assessed cost-effectiveness of adding PAL to usual care in treatment of advanced breast cancer.MethodsWe developed a discrete event simulation model to simulate time to cancer progression and to compare life time clinical benefit and cost of alternative treatment strategies for patients with metastatic disease from societal perspective. Per approved indication, endocrine treatment naive patients were assigned to PAL plus letrozole (PAL + LET) or letrozole alone (LET). Patients with prior endocrine therapy were assigned to PAL plus fulvestrant (FUL) (PAL + FUL) or FUL alone. The model assumptions were informed based on published clinical trial data and other peer reviewed studies. We carried out one-way and probabilistic sensitivity analyses to assess the robustness of our results to the changes in model assumptions.ResultsIn treatment-naive patients, the addition of PAL to LET cost an estimated $768 498 per additional quality-adjusted life-year (QALY) gained. The addition of PAL to FUL in patients with prior endocrine therapy cost an estimated $918 166 per QALY gained. Sensitivity analyses demonstrated adding PAL has a 0% chance of being cost-effectiveness in either patient groups at a willingness-to-pay threshold of $100 000 per QALY.ConclusionFrom a societal perspective, PAL treatment of both patient groups (with and without prior endocrine therapy) is highly unlikely to be cost-effective compared with the usual care in the USA.
      PubDate: 2017-05-02
       
  • Tumor-infiltrating lymphocyte-mediated pleuritis followed by marked
           shrinkage of metastatic kidney cancer of the chest wall during nivolumab
           treatment
    • Authors: Yanagihara TT; Tanaka KK, Ota KK, et al.
      Abstract: Release of the PD-1 immune checkpoint in preexisting tumor-specific T cells leads to cell proliferation and increased effector function. However, the dynamics of tumor-specific T cells after such release have remained largely unknown. Here, we describe a patient with metastatic kidney cancer of the chest wall who developed massive pleural effusion containing predominantly lymphocytes followed by pronounced tumor shrinkage soon after initiation of nivolumab treatment.
      PubDate: 2017-04-29
       
  • The influence of socioeconomic status and ethnicity on adjuvant systemic
           treatment guideline adherence for early-stage breast cancer in the
           Netherlands
    • Authors: Kuijer AA; Verloop JJ, Visser OO, et al.
      Abstract: AbstractBackgroundWe aimed to assess whether socioeconomic status (SES) and ethnicity affect adjuvant systemic therapy (AST) guideline adherence in early breast cancer patients in a health care setting with assumed equal access to care.MethodsData from all female patients surgically treated for primary unifocal early breast cancer between January 2005 and December 2014 were retrieved from the Netherlands Cancer Registry. We assessed the association between SES, ethnicity and non-adherence to adjuvant chemotherapy (CT) or endocrine therapy (ET) guideline indications with Poisson regression models, adjusting for clinicopathological variables.ResultsA total of 104 201 patients were included in the current analysis. Of patients without an indication, 4% and 13% received adjuvant CT or ET (overtreatment), whereas 39% and 14% of patients with an indication did not receive CT or ET (undertreatment). Medium and low SES patients were 1.01 (95% CI 1.00–1.01) and 1.01 (95% CI 1.00–1.01) times more likely to be undertreated and 0.85 (95% CI 0.76–0.94) and 0.67 (95% CI 0.60–0.75) times more likely to be overtreated with CT compared with high SES patients [resulting in an overall relative risk of CT use of 0.94 (95% CI 0.92–0.96) and 0.85 (95% CI 0.83–0.87), respectively]. No association between SES and ET guideline adherence or ethnicity and CT/ET guideline adherence was observed.ConclusionIn the Netherlands, minimal SES disparities in CT guideline adherence were observed: low SES patients are less likely be overtreated and marginally more likely to be undertreated with CT resulting in an overall decreased risk of receiving CT. No ethnical disparities in AST guideline adherence were observed.
      PubDate: 2017-04-29
       
  • Circulating tumor DNA changes for early monitoring of anti-PD1
           immunotherapy: a proof-of-concept study
    • Authors: Cabel LL; Riva FF, Servois VV, et al.
      Abstract: AbstractBackgroundRecent clinical results support the use of new immune checkpoint blockers (ICB), such as anti-PD-1 (e.g. nivolumab and pembrolizumab) and anti-PD-L1 antibodies. Radiological evaluation of ICB efficacy during therapy is challenging due to tumor immune infiltration. Changes of circulating tumor DNA (ctDNA) levels during therapy could be a promising tool for very accurate monitoring of treatment efficacy, but data are lacking with ICB.Patients and methodsThis prospective pilot study was conducted in patients with nonsmall cell lung cancer, uveal melanoma, or microsatellite-instable colorectal cancer treated by nivolumab or pembrolizumab monotherapy at Institut Curie. ctDNA levels were assessed at baseline and after 8 weeks (w8) by bidirectional pyrophosphorolysis-activated polymerization, droplet digital PCR or next-generation sequencing depending on the mutation type. Radiological evaluation of efficacy of treatment was carried out by using immune-related response criteria.ResultsctDNA was detected at baseline in 10 out of 15 patients. At w8, a significant correlation (r = 0.86; P = 0.002) was observed between synchronous changes in ctDNA levels and tumor size. Patients in whom ctDNA levels became undetectable at w8 presented a marked and lasting response to therapy. ctDNA detection at w8 was also a significant prognostic factor in terms of progression-free survival (hazard ratio = 10.2; 95% confidence interval 2.5–41, P < 0.001) and overall survival (hazard ratio = 15; 95% confidence interval 2.5–94.9, P = 0.004).ConclusionThis proof-of-principle study is the first to demonstrate that quantitative ctDNA monitoring is a valuable tool to assess tumor response in patients treated with anti-PD-1 drugs.
      PubDate: 2017-04-29
       
  • German Adjuvant Intergroup Node-positive Study (GAIN): a phase III trial
           comparing two dose-dense regimens (iddEPC versus ddEC-PwX) in high-risk
           early breast cancer patients
    • Authors: Möbus VV; von Minckwitz GG, Jackisch CC, et al.
      Abstract: AbstractBackgroundDose-dense (dd) regimens are one of the preferred options for the adjuvant treatment of breast cancer patients with intermediate to high risk. The German Adjuvant Intergroup Node-positive trial aimed at optimizing intense dd (idd) strategies by evaluating drug combinations and the addition of capecitabine.Patients and methodsWomen (aged 18 years and biologically <65 years) with histologically involved axillary lymph nodes were randomly assigned to receive three courses each of epirubicin (E) 150 mg/m2, paclitaxel (P) 225 mg/m2 and cyclophosphamide (C) 2500 mg/m2 (reduced to 2000 mg/m2 after recruitment of 1200 patients) q2w intravenously (i.v.) (iddEPC-regimen) or ddEC (E 112.5 mg/m2 + C 600 mg/m2, i.v. q2w for 4 cycles) followed by paclitaxel weekly (Pw 67.5 mg/m2 i.v. q8d for 10 weeks) plus capecitabine (X 2000 mg/m2 p.o. days 1–14, q22 for 4 cycles) (ddEC-PwX-regimen). Further randomization assigned patients to ibandronate for 2 years versus observation and to pegfilgrastim day 2 versus 4.ResultsFrom June 2004 to August 2008, 2994 patients were randomized to either iddEPC (N = 1498), or ddEC-PwX (N = 1496) and started treatment. Median age was 50 years; pN1 (37.8%), pN2 (35.3%); pN3 (26.9%); 46.4% were G3 tumors; 76.9% hormone receptor-positive and 22% HER2-positive. After a median follow-up of 74 months, 645 events and 383 deaths were recorded. Hematological adverse events grades 3–4 were more common with iddEPC (P < 0.001), nonhematological with ddEC-PwX (P = 0.04), even if the toxicity profile of the two regimens was different. At 5 years, estimated disease-free survival rates for ddEC-PwX and iddEPC were 81.7% [95% confidence interval (CI) 79.5–83.6] versus 80.2% (95% CI 78.0–82.2). Hazard ratio (HR)=0.95 (95% CI 0.81–1.11, log-rank P = 0.49). Five-year overall survival rates were 89.4% for ddEC-PwX (95% CI 87.7–91.0) and 89.0% for iddEPC (95% CI 87.2–90.6), HR = 0.85 (95% CI 0.69–1.04, log-rank P = 0.10).ConclusionAdding capecitabine to ddEC-Pw did not improve outcome in comparison to iddEPC but increased toxicity and should not be recommended for further use.
      PubDate: 2017-04-28
       
  • Can the FIGO 2000 scoring system for gestational trophoblastic neoplasia
           
    • Authors: Eysbouts YK; Ottevanger PB, Massuger LG, et al.
      Abstract: AbstractBackgroundWorldwide introduction of the International Fedaration of Gynaecology and Obstetrics (FIGO) 2000 scoring system has provided an effective means to stratify patients with gestational trophoblastic neoplasia to single- or multi-agent chemotherapy. However, the system is quite elaborate with an extensive set of risk factors. In this study, we re-evaluate all prognostic risk factors involved in the FIGO 2000 scoring system and examine if simplification is feasible.Patients and methodsBetween January 2003 and December 2012, 813 patients diagnosed with gestational trophoblastic neoplasia were identified at the Trophoblastic Disease Centre in London and scored using the FIGO 2000. Multivariable analysis and stepwise logistic regression were carried out to evaluate whether the FIGO 2000 scoring system could be simplified.ResultsOf the eight FIGO risk factors only pre-treatment serum human chorionic gonadotropin (hCG) levels exceeding 10 000 IU/l (OR = 5.0; 95% CI 2.5–10.4) and 100 000 IU/l (OR = 14.3; 95% CI 4.7–44.1), interval exceeding 7 months since antecedent pregnancy (OR = 4.1; 95% CI 1.0–16.2), and tumor size of over 5 cm (OR = 2.2; 95% CI 1.3–3.6) were identified as independently predictive for single-agent resistance. In addition, increased risk was apparent for antecedent term pregnancy (OR = 3.4; 95% CI 0.9–12.7) and the presence of five or more metastases (OR = 3.5; 95% CI 0.4–30.4), but patient numbers in these categories were relatively small. Stepwise logistic regression identified a simplified risk scoring model comprising age, pretreatment serum hCG, number of metastases, antecedent pregnancy, and interval but omitting tumor size, previous failed chemotherapy, and site of metastases. With this model only 1 out 725 patients was classified different from the FIGO 2000 system.ConclusionOur simplified alternative using only five of the FIGO prognostic factors appears to be an accurate system for discriminating patients requiring single as opposed to multi-agent chemotherapy. Further work is urgently needed to validate these findings.
      PubDate: 2017-04-28
       
  • Prognostic value of MACC1 and proficient mismatch repair status for
           recurrence risk prediction in stage II colon cancer patients: the BIOGRID
           studies
    • Authors: Rohr UP; Herrmann PP, Ilm KK, et al.
      Abstract: AbstractBackgroundWe assessed the novel MACC1 gene to further stratify stage II colon cancer patients with proficient mismatch repair (pMMR).Patients and methodsFour cohorts with 596 patients were analyzed: Charité 1 discovery cohort was assayed for MACC1 mRNA expression and MMR in cryo-preserved tumors. Charité 2 comparison cohort was used to translate MACC1 qRT-PCR analyses to FFPE samples. In the BIOGRID 1 training cohort MACC1 mRNA levels were related to MACC1 protein levels from immunohistochemistry in FFPE sections; also analyzed for MMR. Chemotherapy-naïve pMMR patients were stratified by MACC1 mRNA and protein expression to establish risk groups based on recurrence-free survival (RFS). Risk stratification from BIOGRID 1 was confirmed in the BIOGRID 2 validation cohort. Pooled BIOGRID datasets produced a best effect-size estimate.ResultsIn BIOGRID 1, using qRT-PCR and immunohistochemistry for MACC1 detection, pMMR/MACC1-low patients had a lower recurrence probability versus pMMR/MACC1-high patients (5-year RFS of 92% and 67% versus 100% and 68%, respectively). In BIOGRID 2, longer RFS was confirmed for pMMR/MACC1-low versus pMMR/MACC1-high patients (5-year RFS of 100% versus 90%, respectively). In the pooled dataset, 6.5% of patients were pMMR/MACC1-low with no disease recurrence, resulting in a 17% higher 5-year RFS [95% confidence interval (CI) (12.6%–21.3%)] versus pMMR/MACC1-high patients (P = 0.037). Outcomes were similar for pMMR/MACC1-low and deficient MMR (dMMR) patients (5-year RFS of 100% and 96%, respectively).ConclusionsMACC1 expression stratifies colon cancer patients with unfavorable pMMR status. Stage II colon cancer patients with pMMR/MACC1-low tumors have a similar favorable prognosis to those with dMMR with potential implications for the role of adjuvant therapy.
      PubDate: 2017-04-28
       
  • Impact of physical activity on fatigue and quality of life in people with
           advanced lung cancer: a randomized controlled trial
    • Authors: Dhillon HM; Bell ML, van der Ploeg HP, et al.
      Abstract: AbstractBackgroundPhysical activity (PA) improves fatigue and quality of life (QOL) in cancer survivors. Our aim was to assess whether a 2-month PA intervention improves fatigue and QOL for people with advanced lung cancer.MethodsParticipants with advanced lung cancer, Eastern Cooperative Oncology Group performance status (PS) ≤2, >6 months life expectancy, and ability to complete six-min walk test, were stratified (disease stage, PS 0–1 versus 2, centre) and randomized (1:1) in an open-label study to usual care (UC) (nutrition and PA education materials) or experimental intervention (EX): UC plus 2-month supervised weekly PA and behaviour change sessions. Assessments occurred at baseline, 2, 4, and 6 months. The primary endpoint was fatigue [Functional Assessment of Cancer Therapy-Fatigue (FACT-F) questionnaire] at 2 months. The study was designed to detect a difference in mean FACT-F subscale score of 6. Analysis was intention-to-treat using linear mixed models.ResultsWe recruited 112 patients: 56 (50.4%) were randomized to EX, 55(49.5%) to UC; 1 ineligible. Male 55%; median age 64 years (34–80); 106 (96%) non-small cell lung cancer; 106 (95.5%) stage IV. At 2, 4 and 6 months, 90, 73 and 62 participants were assessed, respectively, with no difference in attrition between groups. There were no significant differences in fatigue between the groups at 2, 4 or 6 months: mean scores at 2 months EX 37.5, UC 36.4 (difference 1.2, 95% CI − 3.5, 5.8, P = 0.62). There were no significant differences in QOL, symptoms, physical or functional status, or survival.ConclusionsAdherence to the intervention was good but the intervention group did not increase their PA enough compared to the control group, and no difference was seen in fatigue or QOL.Trial RegistrationAustralian New Zealand Clinical Trials Registry No. ACTRN12609000971235.
      PubDate: 2017-04-28
       
  • The immune microenvironment of HPV-negative oral squamous cell carcinoma
           from never-smokers and never-drinkers patients suggests higher clinical
           benefit of IDO1 and PD1/PD-L1 blockade
    • Authors: Foy JP; Bertolus CC, Michallet MC, et al.
      Abstract: AbstractBackgroundNever-smokers and never-drinkers patients (NSND) suffering from oral squamous cell carcinoma (OSCC) are epidemiologically different from smokers drinkers (SD). We therefore hypothesized that they harbored distinct targetable molecular alterations.Patients and methodsData from The Cancer Genome Atlas (TCGA) (discovery set), Gene Expression Omnibus and Centre Léon Bérard (CLB) (three validation sets) with available gene expression profiles of HPV-negative OSCC from NSND and SD were mined. Protein expression profiles and genomic alterations were also analyzed from TCGA, and a functional pathway enrichment analysis was carried out. Formalin-fixed paraffin-embedded samples from 44 OSCC including 20 NSND and 24 SD treated at CLB were retrospectively collected to perform targeted-sequencing of 2559 transcripts (HTG EdgeSeq system), and CD3, CD4, CD8, IDO1, and PD-L1 expression analyses by immunohistochemistry (IHC). Enrichment of a six-gene interferon-γ signature of clinical response to pembrozulimab (PD-1 inhibitor) was evaluated in each sample from all cohorts, using the single sample gene set enrichment analysis method.ResultsA total of 854 genes and 29 proteins were found to be differentially expressed between NSND and SD in TCGA. Functional pathway analysis highlighted an overall enrichment for immune-related pathways in OSCC from NSND, especially involving T-cell activation. Interferon-γ response and PD1 signaling were strongly enriched in NSND. IDO1 and PD-L1 were overexpressed and the score of response to pembrolizumab was higher in NSND than in SD, although the mutational load was lower in NSND. IHC analyses in the CLB cohort evidenced IDO1 and PD-L1 overexpression in tumor cells that was associated with a higher rate of tumor-infiltrating T-cells in NSND compared with SD.ConclusionThe main biological and actionable difference between OSCC from NSND and SD lies in the immune microenvironment, suggesting a higher clinical benefit of PD-L1 and IDO1 inhibition in OSCC from NSND.
      PubDate: 2017-04-28
       
  • Disease-free and overall survival at 3.5 years for neoadjuvant bevacizumab
           added to docetaxel followed by fluorouracil, epirubicin and
           cyclophosphamide, for women with HER2 negative early breast cancer:
           ARTemis Trial
    • Authors: Earl HM; Hiller LL, Dunn JA, et al.
      Abstract: AbstractBackgroundThe ARTemis trial previously reported that addition of neoadjuvant bevacizumab (Bev) to docetaxel (D) followed by fluorouracil, epirubicin and cyclophosphamide (D-FEC) in HER2 negative breast cancer improved the pathological complete response (pCR) rate. We present disease-free survival (DFS) and overall survival (OS) with central pathology review.Patients and methodsPatients were randomized to 3 cycles of D followed by 3 cycles of FEC (D-FEC), ±4 cycles of Bev (Bev + D-FEC). DFS and OS were analyzed by treatment and by central pathology reviewed pCR and Residual Cancer Burden (RCB) class.ResultsA total of 800 patients were randomized [median follow-up 3.5 years (IQR 3.2–4.4)]. DFS and OS were similar across treatment arms [DFS hazard ratio (HR)=1.18 (95% CI 0.89–1.57), P = 0.25; OS HR = 1.26 (95% CI 0.90–1.76), P = 0.19). Both local pathology report review and central histopathology review confirmed a significant improvement in DFS and OS for patients who achieved a pCR [DFS HR = 0.38 (95% CI 0.23–0.63), P < 0.001; OS HR = 0.43 (95% CI 0.24–0.75), P = 0.003]. However, significant heterogeneity was observed (P = 0.02); larger improvements in DFS were obtained with a pCR achieved with D-FEC than a pCR achieved with Bev + D-FEC. As RCB class increased, significantly worse DFS and OS was observed (P for trend <0.0001), which effect was most marked in the ER negative group.ConclusionsThe addition of short course neoadjuvant Bev to standard chemotherapy did not demonstrate a DFS or OS benefit. Achieving a pCR with D-FEC is associated with improved DFS and OS but not when pCR is achieved with Bev + D-FEC. At the present time therefore, Bev is not recommended in early breast cancer.ClinicalTrials.gov numberNCT01093235.
      PubDate: 2017-04-27
       
  • Do patient access schemes for high-cost cancer drugs deliver value to
           society'—lessons from the NHS Cancer Drugs Fund
    • Authors: Aggarwal AA; Fojo TT, Chamberlain CC, et al.
      Abstract: AbstractBackgroundThe NHS Cancer Drugs Fund (CDF) was established in 2010 to reduce delays and improve access to cancer drugs, including those that had been previously appraised but not approved by NICE (National Institute for Health and Care Excellence). After 1.3 billion GBP expenditure, a UK parliamentary review in 2016 rationalized the CDF back into NICE.MethodsThis paper analyses the potential value delivered by the CDF according to six value criteria. This includes validated clinical benefits scales, cost-effectiveness criteria as defined by NICE and an assessment of real-world data. The analysis focuses on 29 cancer drugs approved for 47 indications that could be prescribed through the CDF in January 2015.ResultsOf the 47 CDF approved indications, only 18 (38%) reported a statistically significant OS benefit, with an overall median survival of 3.1 months (1.4–15.7 months). When assessed according to clinical benefit scales, only 23 (48%) and 9 (18%) of the 47 drug indications met ASCO and ESMO criteria, respectively. NICE had previously rejected 26 (55%) of the CDF approved indications because they did not meet cost-effectiveness thresholds. Four drugs—bevacizumab, cetuximab, everolimus and lapatinib—represented the bulk of CDF applications and were approved for a total of 18 separate indications. Thirteen of these indications were subsequently delisted by the CDF in January 2015 due to insufficient evidence for clinical benefit—data which were unchanged since their initial approval.ConclusionsWe conclude the CDF has not delivered meaningful value to patients or society. There is no empirical evidence to support a ‘drug only’ ring fenced cancer fund relative to concomitant investments in other cancer domains such as surgery and radiotherapy, or other noncancer medicines. Reimbursement decisions for all drugs and interventions within cancer care should be made through appropriate health technology appraisal processes.
      PubDate: 2017-04-27
       
  • The future of UK healthcare: problems and potential solutions to a system
           in crisis
    • Authors: Montgomery HE; Haines AA, Marlow NN, et al.
      Abstract: AbstractThe UK’s Health System is in crisis, central funding no longer keeping pace with demand. Traditional responses—spending more, seeking efficiency savings or invoking market forces—are not solutions. The health of our nation demands urgent delivery of a radical new model, negotiated openly between public, policymakers and healthcare professionals. Such a model could focus on disease prevention, modifying health behaviour and implementing change in public policy in fields traditionally considered unrelated to health such as transport, food and advertising. The true cost-effectiveness of healthcare interventions must be balanced against the opportunity cost of their implementation, bolstering the central role of NICE in such decisions. Without such action, the prognosis for our healthcare system—and for the health of the individuals it serves—may be poor. Here, we explore such a new prescription for our national health.
      PubDate: 2017-04-27
       
  • Primary tumor sidedness has an impact on prognosis and treatment outcome
           in metastatic colorectal cancer: results from two randomized first-line
           panitumumab studies
    • Authors: Boeckx NN; Koukakis RR, Op de Beeck KK, et al.
      Abstract: AbstractBackgroundPrevious studies have reported the prognostic impact of primary tumor sidedness in metastatic colorectal cancer (mCRC) and its influence on cetuximab efficacy. The present retrospective analysis of two panitumumab trials investigated a possible association between tumor sidedness and treatment efficacy in first-line mCRC patients with RAS wild-type (WT) primary tumors.Materials and methodsData from two randomized first-line panitumumab trials were analyzed for treatment outcomes by primary tumor sidedness for RAS WT patients. PRIME (phase 3; NCT00364013) compared panitumumab plus FOLFOX versus FOLFOX alone; PEAK (phase 2; NCT00819780) compared panitumumab plus FOLFOX versus bevacizumab plus FOLFOX. Primary tumors located in the cecum to transverse colon were coded as right-sided, while tumors located from the splenic flexure to rectum were considered left-sided.ResultsTumor sidedness ascertainment (RAS WT population) was 83% (n = 559/675); 78% of patients (n = 435) had left-sided and 22% (n = 124) had right-sided tumors. Patients with right-sided tumors did worse for all efficacy parameters compared with patients with left-sided disease in the RAS WT population and also in the RAS/BRAF WT subgroup. In patients with left-sided tumors, panitumumab provided better outcomes than the comparator treatment, including on median overall survival (PRIME: 30.3 versus 23.6 months, adjusted hazard ratio = 0.73, P = 0.0112; PEAK: 43.4 versus 32.0 months, adjusted hazard ratio = 0.77, P = 0.3125).ConclusionThe results of these retrospective analyses confirm that in RAS WT patients, right-sided primary tumors are associated with worse prognosis than left-sided tumors, regardless of first-line treatment received. RAS WT patients with left-sided tumors derive greater benefit from panitumumab-containing treatment than chemotherapy alone or combined with bevacizumab, including an overall survival advantage (treatment difference: PRIME 6.7 months; PEAK 11.4 months). No final conclusions regarding optimal treatment could be drawn for RAS WT patients with right-sided mCRC due to the relatively low number of paxtients. Further research in this field is warranted.Trial registration (Clinicaltrials.gov)PRIME (NCT00364013), PEAK (NCT00819780).
      PubDate: 2017-04-25
       
  • Fulvestrant plus LHRH analogues in male with synchronous breast and
           prostate cancer
    • Authors: Martinez Vila CC; Fernández-Morales LA, Oliveres HH, et al.
      Abstract: A 67-year-old man was diagnosed in January 2004 with ductal carcinoma in situ of the right breast. A simple mastectomy with sentinel lymph node biopsy was carried out. Histological examination confirmed a grade III intraductal carcinoma with free margins and no axillary involvement. He received chemoprophylaxis with tamoxifen due to estrogen-receptor positive (ER+) disease. In July 2004, tamoxifen was stopped due to severe hot flashes and myalgias.
      PubDate: 2017-04-24
       
  • Pattern recognition receptors: immune targets to enhance cancer
           immunotherapy
    • Authors: Shekarian TT; Valsesia-Wittmann SS, Brody JJ, et al.
      Abstract: AbstractDurable tumor responses and significant levels of disease control rates have been described in more than 20 advanced/metastatic cancer types with B7-family immune checkpoint-targeted anti-CTLA-4, anti-PD-1, and anti-PD-L1 monoclonal antibodies. These results and the recent approvals of ipilimumab, pembrolizumab, nivolumab and atezolizumab are currently revolutionizing the way we envision the future of cancer care. However these clinical benefits are not observed in all cancer types and in every patient. Therefore, our clinical challenge is to identify therapeutic strategies which could overcome the primary and secondary resistances to these novel cancer immunotherapies. Pattern recognition receptors (PRRs) are other critical costimulatory molecules of immune cells, notably myeloid cells (macrophages and dendritic cells). They were initially described as sensors for ‘danger signals’ released by pathogens (e.g. viral DNA and bacterial proteins). We know now that PRRs can also be recruited and activated upon recognition of endogenous stress signals such as molecules released upon self-cell death (e.g. ATP and HMGB1). Natural endo/exogenous or synthetic PRRs agonists have notably the ability to activate phagocytosis and antigen presentation by myeloid cells residing in the tumor micro-environment. In pre-clinical models, these PRRs agonists have also been shown to overcome the resistance to T-cell targeted immune checkpoints anti-CTLA-4 and anti-PD-1/PD-L1. This manuscript reviews the current knowledge on this major family of immune receptors and the molecules targeting them which are currently in clinical development.
      PubDate: 2017-04-21
       
  • FGFR2 amplification in metastatic hormone-positive breast cancer and
           response to an mTOR inhibitor
    • Authors: Wein LL; Savas PP, Van Geelen CC, et al.
      Abstract: Fibroblast growth factor receptors (FGFR) and their ligands (FGF) play an important role in proliferation, migration, angiogenesis, and survival of cancer cells [1]. High-level amplification of FGFR2 has been shown to initiate distinct signalling characterized by transactivation of alternative receptor tyrosine kinases to bring PI3K and mTOR signalling under control of FGFR2 [2]. This case report describes a patient with estrogen receptor (ER)-positive metastatic breast cancer with a high level FGFR2 gene amplification who demonstrated a significant clinical benefit to an mTOR inhibitor, everolimus with exemestane.
      PubDate: 2017-04-18
       
  • Reply to the letter to the editor ‘Addressing the quality of the
           ESMO-MCBS’ by Del Paggio
    • Authors: Cherny NI; Dafni UU, Bogaerts JJ, et al.
      Abstract: Dr Del Paggio [1] is correct in his observation that the ESMO-MCBS incorporates an evidence based approach regarding the limited reliability of progression-free survival (PFS) as a surrogate for either overall survival (OS) or improvement in quality of life (QoL). Consequently, in studies incorporating PFS as a primary endpoint, optimal ESMO-MCBS grading, namely a 4, can only be achieved if surrogacy is verified either by demonstrating survival gain or QoL advantage (either improved QoL or delayed deterioration in QoL) [2].
      PubDate: 2017-04-18
       
  • QoL is a cool tool
    • Authors: Procaccio LL; Lonardi SS, Loupakis FF, et al.
      Abstract: We read the manuscript by Dr Schuurhuizen et al., questioning the validity of the global quality of life (QoL) measurements in metastatic colorectal cancer (mCRC) [1].
      PubDate: 2017-04-18
       
  • Prognostic and predictive value of primary tumour side in patients with
           RAS wild-type metastatic colorectal cancer treated with chemotherapy and
           EGFR directed antibodies in six randomized trials †
    • Authors: Arnold DD; Lueza BB, Douillard JY, et al.
      Abstract: AbstractBackgroundThere is increasing evidence that metastatic colorectal cancer (mCRC) is a genetically heterogeneous disease and that tumours arising from different sides of the colon (left versus right) have different clinical outcomes. Furthermore, previous analyses comparing the activity of different classes of targeted agents in patients with KRAS wild-type (wt) or RAS wt mCRC suggest that primary tumour location (side), might be both prognostic and predictive for clinical outcome.MethodsThis retrospective analysis investigated the prognostic and predictive influence of the localization of the primary tumour in patients with unresectable RAS wt mCRC included in six randomized trials (CRYSTAL, FIRE-3, CALGB 80405, PRIME, PEAK and 20050181), comparing chemotherapy plus EGFR antibody therapy (experimental arm) with chemotherapy or chemotherapy and bevacizumab (control arms). Hazard ratios (HRs) and 95% confidence intervals (CIs) for overall survival (OS) and progression-free survival (PFS) for patients with left-sided versus right-sided tumours, and odds ratios (ORs) for objective response rate (ORR) were estimated by pooling individual study HRs/ORs. The predictive value was evaluated by pooling study interaction between treatment effect and tumour side.ResultsPrimary tumour location and RAS mutation status were available for 2159 of the 5760 patients (37.5%) randomized across the 6 trials, 515 right-sided and 1644 left-sided. A significantly worse prognosis was observed for patients with right-sided tumours compared with those with left-sided tumours in both the pooled control and experimental arms for OS [HRs = 2.03 (95% CI: 1.69–2.42) and 1.38 (1.17–1.63), respectively], PFS [HRs = 1.59 (1.34–1.88) and 1.25 (1.06–1.47)], and ORR [ORs = 0.38 (0.28–0.50) and 0.56 (0.43–0.73)]. In terms of a predictive effect, a significant benefit for chemotherapy plus EGFR antibody therapy was observed in patients with left-sided tumours [HRs = 0.75 (0.67–0.84) and 0.78 (0.70–0.87) for OS and PFS, respectively] compared with no significant benefit for those with right-sided tumours [HRs = 1.12 (0.87–1.45) and 1.12 (0.87–1.44) for OS and PFS, respectively; P value for interaction <0.001 and 0.002, respectively]. For ORR, there was a trend (P value for interaction = 0.07) towards a greater benefit for chemotherapy plus EGFR antibody therapy in the patients with left-sided tumours [OR = 2.12 (1.77–2.55)] compared with those with right-sided tumours [OR = 1.47 (0.94–2.29)]. Exclusion of the unique phase II trial or the unique second-line trial had no impact on the results. The predictive effect on PFS may depend of the type of EGFR antibody therapy and on the presence or absence of bevacizumab in the control arm.ConclusionThis pooled analysis showed a worse prognosis for OS, PFS and ORR for patients with right-sided tumours compared with those with left-sided tumours in patients with RAS wt mCRC and a predictive effect of tumour side, with a greater effect of chemotherapy plus EGFR antibody therapy compared with chemotherapy or chemotherapy and bevacizumab, the effect being greatest in patients with left-sided tumours. These predictive results should be interpreted with caution due to the retrospective nature of the analysis, which was carried out on subpopulations of patients included in these trials, and because none of these studies contemplated a full treatment sequence strategy.
      PubDate: 2017-04-12
       
  • Foods and beverages and colorectal cancer risk: a systematic review and
           meta-analysis of cohort studies, an update of the evidence of the
           WCRF-AICR Continuous Update Project
    • Authors: Vieira AR; Abar LL, Chan DM, et al.
      Abstract: AbstractObjectiveAs part of the World Cancer Research Fund International Continuous Update Project, we updated the systematic review and meta-analysis of prospective studies to quantify the dose–response between foods and beverages intake and colorectal cancer risk.Data sourcesPubMed and several databases up to 31 May 2015.Study selectionProspective studies reporting adjusted relative risk estimates for the association of specific food groups and beverages and risk of colorectal, colon and rectal cancer.Data synthesisDose–response meta-analyses using random effect models to estimate summary relative risks (RRs).ResultsAbout 400 individual study estimates from 111 unique cohort studies were included. Overall, the risk increase of colorectal cancer is 12% for each 100 g/day increase of red and processed meat intake (95% CI = 4–21%, I2=70%, pheterogeneity (ph)<0.01) and 7% for 10 g/day increase of ethanol intake in alcoholic drinks (95% CI = 5–9%, I2=25%, ph = 0.21). Colorectal cancer risk decrease in 17% for each 90g/day increase of whole grains (95% CI = 11–21%, I2 = 0%, ph = 0.30, 6 studies) and 13% for each 400 g/day increase of dairy products intake (95% CI = 10–17%, I2 = 18%, ph = 0.27, 10 studies). Inverse associations were also observed for vegetables intake (RR per 100 g/day =0.98 (95% CI = 0.96–0.99, I2=0%, ph = 0.48, 11 studies) and for fish intake (RR for 100 g/day = 0.89 (95% CI = 0.80–0.99, I2=0%, ph = 0.52, 11 studies), that were weak for vegetables and driven by one study for fish. Intakes of fruits, coffee, tea, cheese, poultry and legumes were not associated with colorectal cancer risk.ConclusionsOur results reinforce the evidence that high intake of red and processed meat and alcohol increase the risk of colorectal cancer. Milk and whole grains may have a protective role against colorectal cancer. The evidence for vegetables and fish was less convincing.
      PubDate: 2017-04-12
       
  • Drug-induced liver injury in Oncology
    • Authors: Ricart AD.
      Abstract: Although serious drug-related hepatotoxicity is uncommon, it has been the most frequent single cause of safety-related drug marketing withdrawals according to the US Food and Drug Administration (FDA) [1]. The regenerative properties of the liver are also uncommon for an internal organ [2]. Being located between the gastrointestinal tract and the ‘central compartment’ of foreign substances (including drugs), the liver is essential to metabolism and detoxification. Liver regeneration has been an adaptation of vertebrates through evolutionary events to protect them from environmental pressures (e.g. ingested toxins). It was eloquently described by the ancient Greeks in the myth of Prometheus.
      PubDate: 2017-04-05
       
  • Statistical controversies in clinical research: data access and
           sharing—can we be more transparent about clinical research' Let’s
           do what’s right for patients
    • Authors: Rockhold FW.
      Abstract: AbstractCalls for greater transparency and ‘open data access’ in clinical research are widespread, from sources including the Executive Office of the President, which in 2013 called for increased access to the results of federally funded research. In 2015, The Institute of Medicine issued a report advocating for a multi-stakeholder effort to foster responsible data sharing, and there are many others. Open science is good for researchers, good for innovation, and good for patients. The question at the center of the open-science efforts for clinical trials should not be whether data should be shared, but rather how we can usher in responsible methods for doing so. Unfortunately, there remain numerous perceived barriers to complete transparency around clinical trial data. This paper reviews the current status of data disclosure, the barriers to achieving it and a suggestion for the future.
      PubDate: 2017-04-05
       
  • Blinatumomab (Blincyto): lessons learned from the bispecific t-cell
           engager (BiTE) in acute lymphocytic leukemia (ALL)
    • Authors: Friberg GG; Reese DD.
      Abstract: A BiTE® is a bispecific antibody construct with specificity for CD3 on the T cell and a selected surface antigen on a tumor cell [1]. When infused into patients, these antibodies are capable of eliciting polyclonal T cell responses that are unrestricted by T cell receptor specificity, presence of MHC class, or additional T cell co-stimuli [2]. The most clinically advanced of these molecules is the CD19/CD3 bispecific blinatumomab (Blincyto®), which was approved for the treatment of adult relapsed/refractory (R/R) Philadelphia negative (Ph-) B cell precursor ALL in the US and EU in December 2014 and December 2015, respectively [3]. These approvals highlight the potential for a T-cell engaging therapy in ALL patients, as well as the willingness of regulatory authorities to swiftly advance such therapies via accelerated mechanisms in orphan indications with significant unmet need. Two years after these accelerated/conditional approvals in relapsed/refractory ALL, randomized data confirmed that blinatumomab provided a statistically significant overall survival advantage compared to standard chemotherapy, nearly doubling the median survival times [4].
      PubDate: 2017-03-31
       
  • Cancer drug costs—the case for a thoughtful discussion of a
           manageable problem
    • Authors: Dhingra KK.
      Abstract: Rapid advances in our understanding of the biology driving the neoplastic process are translating into a dramatic increase in the number of available treatment options for cancer. These therapies can lead to longer duration and better quality of responses, even in patients with advanced disease. Concern about the cost of cancer drugs and the value they provide has existed for a long time, even during the era when chemotherapy drugs were largely the only systemic modality of cancer therapy for most patients. Ironically, these concerns have assumed a greater urgency, in part, because the superior efficacy of newer drugs is translating to more lines of therapy as well as greater duration of each line of therapy. In parallel, the generally rising cost of healthcare, and certain high-profile pharmaceuticals in particular, in oncology and elsewhere has shone a spotlight on the costs to society of the current healthcare economic paradigms [1, 2].
      PubDate: 2017-03-27
       
  • Statistical controversies in cancer research: using standardized effect
           size graphs to enhance interpretability of cancer-related clinical trials
           with patient-reported outcomes
    • Authors: Bell ML; Fiero MH, Dhillon HM, et al.
      Abstract: AbstractPatient reported outcomes (PROs) are becoming increasingly important in cancer studies, particularly with the emphasis on patient centered outcome research. However, multiple PROs, using different scales, with different directions of favorability are often used within a trial, making interpretation difficult. To enhance interpretability, we propose the use of a standardized effect size graph, which shows all PROs from a study on the same figure, on the same scale. Plotting standardized effects with their 95% confidence intervals (CIs) on a single graph clearly showing the null value conveys a comprehensive picture of trial results. We demonstrate how to create such a graph using data from a randomized controlled trial that measured 12 PROs at two time points. The 24 effect sizes and CIs are shown on one graph and clearly indicate that the intervention is effective and sustained.
      PubDate: 2017-03-06
       
  • New agents on the horizon in gastric cancer
    • Authors: Lordick FF; Shitara KK, Janjigian YY.
      Abstract: AbstractBackgroundConventional cytotoxic chemotherapy has been the backbone of advanced gastric cancer treatment for decades and still represents a key element of the therapeutic armamentarium. However, only small increments in survival outcomes have been reached. A better understanding of genetic alterations and molecular signatures of gastric cancer has been reached in the last years. It will serve as a roadmap for better treatment stratification and future drug development.Materials and methodsWe reviewed preclinical and clinical studies that assessed novel treatment targets and emerging drug therapies in gastric cancer. We performed research via PubMed, and the congress webpages of the American Society of Clinical Oncology, European Society of Medical Oncology and the Japanese Society of Medical Oncology.ResultsHER2-targeting with trastuzumab is effective in HER2-positive metastatic gastric cancer; combined HER2 targeting strategies are being investigated. Studies assessing the role of HER2 targeting in the perioperative setting are ongoing. Novel treatment targets include inhibition of cancer stemness-related signaling pathways like STAT3. DNA damage repair and Claudin 18.2, a tight junction protein with high expression in gastric cancers are also novel molecular drug targets. Modification of the tumor microenvironment, including activation of immune response by PD-1/PD-L1 checkpoint inhibitors and stroma modification by matrix metalloproteinase-9 inhibition, led to first promising treatment results.ConclusionNovel treatment options for gastric cancer patients are emerging. They involve novel mechanisms of action, and are based on our constantly increasing understanding of tumor biology and better molecular stratification of gastric cancer patients.
      PubDate: 2017-02-09
       
 
 
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