Ian F Tannock

University of Toronto, Toronto, Ontario, Canada

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Publications (392)3809.42 Total impact

  • Saroj Niraula · Ian F Tannock

    No preview · Article · Dec 2015
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    Ian Tannock · Cora N. Sternberg

    Preview · Article · Dec 2015 · Annals of Oncology
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    Andrea S Fung · Carol Lee · Man Yu · Ian F Tannock
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    ABSTRACT: The growth of solid tumors and their regrowth after treatment is dependent upon functional tumor vasculature. Some chemotherapeutic agents have shown anti-angiogenic properties but there are limited studies of the effect of chemotherapy on tumor vasculature. Here we investigate the effect of paclitaxel, 5-fluorouracil (5-FU) and doxorubicin on tumor vasculature in subcutaneous and orthotopic xenografts in mice The vascular density and percentage of functional blood vessels were evaluated in subcutaneous A431 human vulvar cancer xenografts, and in subcutaneous and orthotopic MCF-7 human breast cancer xenografts, following single doses of paclitaxel, 5-FU or doxorubicin There was no significant difference in total (CD31+) blood vessels between untreated ectopic and orthotopic MCF-7 tumors, but there was a significantly lower proportion of functional blood vessels in orthotopic tumors. After paclitaxel treatment, there was a decrease in functional tumor vasculature in A431 subcutaneous xenografts, followed by a subsequent rebound. There was a significant decrease in total vascular density on day 12 in A431 tumors following 5-FU or doxorubicin treatment, but no change in the percentage of functional vessels. An increase in functional blood vessels or percentage of functional vasculature was noted in MCF-7 subcutaneous and orthotopic xenografts following chemotherapy treatment There are differences in the vasculature and microenvironment of ectopic and orthotopic xenografts in mice. Anti-tumor effects of chemotherapy may be due, in part, to effects on tumor vasculature and may vary in different tumor models.
    Preview · Article · Dec 2015 · BMC Cancer
  • B. Seruga · A. Ocana · E. Amir · I. F. Tannock
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    ABSTRACT: Phase III randomized controlled trials (RCT) in oncology fail to lead to registration of new therapies more often than RCTs in other medical disciplines. Most RCTs are sponsored by the pharmaceutical industry, which reflects industry's increasing responsibility in cancer drug development. Many preclinical models are unreliable for evaluation of new anticancer agents, and stronger evidence of biologic effect should be required before a new agent enters the clinical development pathway. Whenever possible, early-phase clinical trials should include pharmacodynamic studies to demonstrate that new agents inhibit their molecular targets and demonstrate substantial antitumor activity at tolerated doses in an enriched population of patients. Here, we review recent RCTs and found that these conditions were not met for most of the targeted anticancer agents, which failed in recent RCTs. Many recent phase III RCTs were initiated without sufficient evidence of activity from earlyphase clinical trials. Because patients treated within such trials can be harmed, they should not be undertaken. The bar should also be raised when making decisions to proceed from phase II to III and from phase III to marketing approval. Many approved agents showed only better progression-free survival than standard treatment in phase III trials and were not shown to improve survival or its quality. Introduction of value-based pricing of new anticancer agents would dissuade the continued development of agents with borderline activity in early-phase clinical trials. When collaborating with industry, oncologists should be more critical and better advocates for cancer patients.
    No preview · Article · Oct 2015 · Clinical Cancer Research
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    ABSTRACT: BACKGROUND: Androgen deprivation therapy (ADT) with luteinizing hormone releasing hormone (LHRH) agonists is an effective initial therapy for men with advanced prostate cancer. LHRH agonists are usually administered indefinitely at a fixed interval. METHODS: We recruited men with advanced prostate cancer who had been on fixed-schedule injections of an LHRH agonist for ≥1 year and had castrate serum testosterone [<1.75nmol/l (approx. 50ng/ml)]. Testosterone levels were measured at 6-week intervals and ADT was withheld until testosterone levels were no longer in the castrate range and then reinstituted. Time to reinstitution of ADT was the primary outcome and was analyzed by the Kaplan-Meier method; Cox regression was used to identify factors predicting delay in reinstitution of treatment. Influence on quality-of-life (QoL) was evaluated by the Expanded Prostate Index Composite (EPIC). RESULTS: Forty-six evaluable men who had received LHRH agonist injections every 12 weeks were recruited. Median time to testosterone recovery (defined as testosterone outside the defined castrate level) after previous injection was >1 year. In univariable analysis, lower baseline testosterone [≤1 vs. >1nmol/l (approx. 30ng/dl)] and longer time on ADT (>5 vs. ≤5 years) predicted for prolonged time to testosterone recovery, but only lower baseline testosterone remained significant in multivariable analysis (Hazard Ratio=5.2, P=0.03). Overall EPIC scores remained stable but improvement from baseline was observed in the hormonal domain (P=0.002). Median per-patient saving in cost was approximately USD 3,100 (1,050-6,200). CONCLUSIONS: Testosterone-guided ADT reduces exposure to LHRH agonists, with reduction in cost and improvement in some symptoms from ADT. Testosterone-guided ADT should be considered an alternative to fixed schedule treatment by physicians and policy makers.
    No preview · Article · Oct 2015 · The Prostate

  • No preview · Poster · Sep 2015

  • No preview · Poster · Sep 2015
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    Man Yu · Carol Lee · Marina Wang · Ian F Tannock
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    ABSTRACT: Cellular causes of resistance and limited drug distribution within solid tumors limit therapeutic efficacy of anticancer drugs. Acidic endosomes in cancer cells mediate autophagy, which facilitates survival of stressed cells, and may contribute to drug resistance. Basic drugs (e.g. doxorubicin) are sequestered in acidic endosomes, thereby diverting drugs from their target DNA and decreasing penetration to distal cells. Proton pump inhibitors (PPIs) may raise endosomal pH, with potential to improve drug efficacy and distribution in solid tumors. We determined effects of the PPI, lansoprazole, to modify the activity of doxorubicin. To gain insight into mechanisms, we studied effects of lansoprazole on endosomal pH, and on the spatial distribution of doxorubicin, and of biomarkers reflecting its activity, using in vitro and murine models. Lansoprazole displayed concentration-dependent effects to raise endosomal pH and to inhibit endosomal sequestration of doxorubicin in cultured tumor cells. Lansoprazole was not toxic to cancer cells but potentiated the cytotoxicity of doxorubicin and enhanced its penetration through multilayered cell cultures. In solid tumors, lansoprazole improved the distribution of doxorubicin but also increased expression of biomarkers of drug activity throughout the tumor. Combined treatment with lansoprazole and doxorubicin was more effective in delaying tumor growth as compared to either agent alone. Together, lansoprazole enhances therapeutic effects of doxorubicin both by improving its distribution and increasing its activity in solid tumors. Use of PPIs to improve drug distribution and to inhibit autophagy represents a promising strategy to enhance the effectiveness of anticancer drugs in solid tumors. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Preview · Article · Jul 2015 · Cancer Science
  • Qian Tan · Jasdeep K Saggar · Man Yu · Marina Wang · Ian F Tannock
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    ABSTRACT: Drug resistance can occur at the individual cellular level or as a result of properties of the tumor microenvironment. The convoluted vasculature within tumors results in robustly proliferating well-nourished cells located proximal to functional blood vessels and regions of slowly proliferating (often hypoxic) cells located distal to functional blood vessels. Irregular blood flow and large distances between functional blood vessels in solid tumors lead to poor drug distribution within them such that cells distal from functional blood vessels are exposed to ineffective concentrations of drug, resulting in therapeutic resistance. Strategies to improve or complement the distribution of anticancer drugs within tumors hold promise for increasing antitumor effects without corresponding increases in normal tissue toxicity. In particular, use of hypoxia-targeted agents and modulation of autophagy have shown promising results in enhancing the distribution of drug activity within solid tumors and hence antitumor efficacy. In this review, we describe causes of resistance to chemotherapy that relate to the microenvironment of solid tumors and the potential to improve antitumor effects by countering such mechanisms of resistance.
    No preview · Article · Jul 2015 · The Cancer Journal

  • No preview · Conference Paper · Jun 2015
  • Christopher M Booth · Ian F Tannock

    No preview · Article · Jun 2015
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    ABSTRACT: The mechanisms underlying the favourable prognosis of androgen receptor (AR) expression in breast cancer are unknown. The associations between the 21-gene recurrence score (RS), AR, grade, mitotic score, Ki-67 and estrogen receptor (ER) and progesterone receptor (PgR) expression were explored in sequential women with lymph node-negative, ER-positive and HER2-negative breast cancer. Statistical significance of this exploratory study was defined as p<0.10. Analysis comprised 70 women. Most tumours had high AR expression (97% had scores >3). Median RS was 15 (range 1-53). AR expression showed a minimally significant positive correlation with ER (R=0.37), but no correlation with Ki-67 (R=-0.18). In univariable analysis, AR (p=0.01), ER (p<0.001) and PgR (p<0.001) had significant negative associations with RS. Ki-67 (p=0.16), grade (p=0.40) and mitotic score (p=0.23) showed no association with RS. Multivariable analysis showed similar associations. AR is associated with lower RS, but not with Ki-67. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
    No preview · Article · Jun 2015 · Journal of clinical pathology
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    ABSTRACT: Much progress has been made in research for prostate cancer in the past decade. There is now greater understanding for the genetic basis of familial prostate cancer with identification of rare but high-risk mutations (eg, BRCA2, HOXB13) and low-risk but common alleles (77 identified so far by genome-wide association studies) that could lead to targeted screening of patients at risk. This is especially important because screening for prostate cancer based on prostate-specific antigen remains controversial due to the high rate of overdiagnosis and unnecessary prostate biopsies, despite evidence that it reduces mortality. Classification of prostate cancer into distinct molecular subtypes, including mutually exclusive ETS-gene-fusion-positive and SPINK1-overexpressing, CHD1-loss cancers, could allow stratification of patients for different management strategies. Presently, men with localised disease can have very different prognoses and treatment options, ranging from observation alone through to radical surgery, with few good-quality randomised trials to inform on the best approach for an individual patient. The survival of patients with metastatic prostate cancer progressing on androgen-deprivation therapy (castration-resistant prostate cancer) has improved substantially. In addition to docetaxel, which has been used for more than a decade, in the past 4 years five new drugs have shown efficacy with improvements in overall survival leading to licensing for the treatment of metastatic castration-resistant prostate cancer. Because of this rapid change in the therapeutic landscape, no robust data exist to inform on the selection of patients for a specific treatment for castration-resistant prostate cancer or the best sequence of administration. Moreover, the high cost of the newer drugs limits their widespread use in several countries. Data from continuing clinical and translational research are urgently needed to improve, and, crucially, to personalise management.
    Full-text · Article · Jun 2015 · The Lancet
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    ABSTRACT: Full Text Avail for Limited Time: http://authors.elsevier.com/a/1RCcR_3r0J3Zr7 The heterogeneous intra-tumoral accumulation of liposomes has been linked to both the chaotic tumor microcirculation and to elevated interstitial fluid pressure (IFP). Here, we explored the relationship between tumor microcirculation, IFP, and the intra-tumoral accumulation of liposomes. Measurements of the tumor microcirculation using perfusion imaging, IFP using a novel image-guided robotic needle positioning system, and the intra-tumoral distribution of liposomes using volumetric micro-CT imaging were performed in mice bearing subcutaneous and orthotopic MDA-MB-231 tumors. Intra-tumoral perfusion and IFP were substantially different between the two tumor implantation sites. Tumor perfusion and not vascular permeability was found to be the primary mediator of the intra-tumoral accumulation of CT-liposomes. A strong relationship was observed between the radial distribution of IFP, metrics of tumor perfusion, and the intra-tumoral accumulation of liposomes. Tumors with elevated central IFP that decreased at the periphery had low perfusion and low levels of CT-liposome accumulation that increased towards the periphery. Conversely, tumors with low and radially uniform IFP exhibited higher levels of tumor perfusion and CT-liposome accumulation. Both tumor perfusion and elevated IFP exhibit substantial intra-tumoral heterogeneity and both play an integral role in mediating the intra-tumoral accumulation of liposomes through a complex interactive effect. Measuring IFP in the clinical setting remains challenging and these results demonstrate that tumor perfusion imaging alone provides a robust non-invasive method to identify factors that contribute to poor liposome accumulation and may allow for pre-selection of patients that are more likely to respond to nanoparticle therapy. Copyright © 2015. Published by Elsevier B.V.
    No preview · Article · Jun 2015 · Journal of Controlled Release
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    ABSTRACT: The first St.Gallen Advanced Prostate Cancer Consensus Conference (APCCC) Expert Panel identified and reviewed the available evidence for the ten most important areas of controversy in advanced prostate cancer management. The successful registration of several drugs for castration-resistant prostate cancer and the recent studies of chemo-hormonal therapy in men with castration-naïve prostate cancer have led to considerable uncertainty as to the best treatment choices, sequence of treatment options and appropriate patient selection.Management recommendations based on expert opinion, and not based on a critical review of the available evidence, are presented. The various recommendations carried differing degrees of support, as reflected in the wording of the article text and in the detailed voting results recorded in supplementary material, available at Annals of Oncology online. Detailed decisions on treatment as always will involve consideration of disease extent and location, prior treatments, host factors, patient preferences as well as logistical and economic constraints. Inclusion of men with advanced prostate cancer in clinical trials should be encouraged. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.
    Full-text · Article · Jun 2015 · Annals of Oncology

  • No preview · Conference Paper · May 2015
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    K Fizazi · C Jenkins · I F Tannock
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    ABSTRACT: Following the results of the TAX-327 study, questions have been raised as to whether administering chemotherapy to men with prostate cancer before symptomatic disease progression when receiving standard hormonal treatment can improve the duration and quality of patient survival. The GETUG-AFU-15 and CHAARTED studies both assessed the efficacy and tolerability of androgen deprivation therapy (ADT) with or without docetaxel in men with metastatic hormone-naive prostate cancer. Both studies included a mix of patients with de novo metastatic disease (∼75%) and patients who developed metastases following treatment for localized disease. A short course of ADT was allowed in both trials prior to accrual. Key differences between the two studies include the number of patients with high-volume metastases (GETUG-AFU-15: 52%; CHAARTED: 65%) and number of docetaxel cycles (GETUG-AFU-15: up to 9 cycles; CHAARTED 6 cycles). Both studies reported an improvement in progression-free survival with docetaxel plus ADT vs ADT alone. The GETUG-AFU-15 did not find a significant difference in the primary endpoint of overall survival (hazard ratio [HR] 0.9 [95% Confidence Interval [CI] 0.7, 1.2; P=0.44) for ADT plus docetaxel vs ADT alone. The CHAARTED study met the primary endpoint of overall survival (HR 0.61 [95% CI 0.47, 0.80]; P=0.0003), and in a subset analysis reported the greatest improvement in overall survival for patients with high-volume disease (HR 0.60 [95% CI 0.45, 0.81] P=0.0006). The following article debates the results from the GETUG-AFU-15 and CHAARTED studies and asks whether medical practice should be changed for patients with metastatic hormone-naive prostate cancer based on the results of one positive study. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.
    Preview · Article · May 2015 · Annals of Oncology
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    ABSTRACT: This study examined the impact of androgen-deprivation therapy (ADT) on physical function and quality of life (QOL) over 36 months. Eighty-seven men with nonmetastatic prostate cancer (PC) who were starting continuous ADT and 2 control groups (86 PC controls without ADT and 86 healthy controls), matched by age and education, were enrolled. Physical function was assessed with the 6-minute walk test (6MWT), grip strength, and Timed Up and Go (TUG) test. QOL was measured with the 36-Item Short Form Health Survey of the Medical Outcomes Study. Subjects were assessed at the baseline and at 3, 6, 12, 18, 24, 30, and 36 months. Mixed effects regression models were fitted with adjustments for baseline covariates. The 6MWT distance improved initially and then stabilized in both control groups but remained unchanged for ADT users (P = .0030). Grip strength remained stable in control groups but declined sharply in the ADT group by 3 months and then remained stable to 36 months (P = .0041). TUG scores declined gradually in the ADT group over 36 months but were unchanged in control groups (P = .0008). Aggregate physical QOL declined in ADT users over time but remained stable in control groups (P = .0001). Aggregate mental QOL was stable in all groups. Declines seen in the first year of ADT use generally persisted over 36 months and were independent of age. Previously noted physical side effects over the first 12 months of ADT persisted or continued to worsen over an additional 2 years with no evidence of recovery. Exercise interventions to counteract these declines may be warranted. Cancer 2015. © 2015 American Cancer Society. © 2015 American Cancer Society.
    No preview · Article · Mar 2015 · Cancer
  • I. Tannock · M. Toi · L.W. Chow

    No preview · Article · Mar 2015 · The International journal of biological markers
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    ABSTRACT: Progression-free survival and time-to-progression (PFS/TTP) are used commonly as primary end-points in trials evaluating treatments for metastatic breast cancer (MBC). We reviewed the impact of censoring on interpretation of these end-points. A systematic review identified phase 3 trials in MBC published between 2001 and 2012 that reported hazard ratios (HRs) for PFS/TTP and Kaplan-Meier curves indicating numbers at risk. We calculated HRs for time-to-treatment-failure (TTF) where discontinuation of treatment for any reason is considered an event. Mean HRs for PFS/TTP, TTF, and overall survival (OS) were 0.79, 0.89 and 0.91, respectively. Unbalanced censoring of patients prior to progression was prevalent, usually with more patients censored in the experimental arms. There was moderate-to-poor correlation of HRs of PFS/TTP and TTF with HRs for OS. We suggest that TTF should be reported as supportive analysis in registration trials and extent of missing data due to censoring be considered in decisions made by regulatory agencies. Copyright © 2015 Elsevier Ltd. All rights reserved.
    No preview · Article · Feb 2015 · European journal of cancer (Oxford, England: 1990)

Publication Stats

22k Citations
3,809.42 Total Impact Points


  • 1984-2015
    • University of Toronto
      • • Department of Medical Biophysics
      • • Department of Medicine
      Toronto, Ontario, Canada
  • 1981-2015
    • The Princess Margaret Hospital
      Toronto, Ontario, Canada
  • 2002-2014
    • University Health Network
      • Department of Medical Oncology
      Toronto, Ontario, Canada
  • 2013
    • Erasmus MC
      Rotterdam, South Holland, Netherlands
    • National Cancer Institute (USA)
      Maryland, United States
  • 2008
    • Queen's University
      Kingston, Ontario, Canada
  • 2003
    • Centre Léon Bérard
      Lyons, Rhône-Alpes, France
  • 1983-1998
    • Ontario Institute for Cancer Research
      Toronto, Ontario, Canada