Jennifer J Knox

The Princess Margaret Hospital, Toronto, Ontario, Canada

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Publications (101)471.73 Total impact

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    ABSTRACT: Background:Limited data exist on outcomes for metastatic renal cell carcinoma (mRCC) patients treated with multiple lines of therapy. Benchmarks for survival are required for patient counselling and clinical trial design.Methods:Outcomes of mRCC patients from the International mRCC Database Consortium database treated with 1, 2, or 3+ lines of targeted therapy (TT) were compared by proportional hazards regression. Overall survival (OS) and progression-free survival (PFS) were calculated using different population inclusion criteria.Results:In total, 2705 patients were treated with TT of which 57% received only first-line TT, 27% received two lines of TT, and 16% received 3+ lines of TT. Overall survival of patients who received 1, 2, or 3+ lines of TT were 14.9, 21.0, and 39.2 months, respectively, from first-line TT (P<0.0001). On multivariable analysis, 2 lines and 3+ lines of therapy were each associated with better OS (HR=0.738 and 0.626, P<0.0001). Survival outcomes for the subgroups were as follows: for all patients, OS 20.9 months and PFS 7.2 months; for those similar to eligible patients in the first-line ADAPT trial, OS 14.7 months and PFS 5.6 months; for those similar to patients in first-line TIVO-1 trial, OS 24.8 months and PFS 8.2 months; for those similar to patients in second-line INTORSECT trial, OS 13.0 months and PFS 3.9 months; and for those similar to patients in the third-line GOLD trial, OS 18.0 months and PFS 4.4 months.Conclusions:Patients who are able to receive more lines of TT live longer. Survival benchmarks provide context and perspective when interpreting and designing clinical trials.British Journal of Cancer advance online publication, 1 April 2014; doi:10.1038/bjc.2014.25 www.bjcancer.com.
    British Journal of Cancer 04/2014; · 5.08 Impact Factor
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    ABSTRACT: Brahma (BRM) has a key function in chromatin remodeling. Two germline BRM promoter insertion-deletion polymorphisms, BRM-741 and BRM-1321, have been previously associated with an increased risk of lung cancer in smokers and head and neck cancer. To further evaluate their role in cancer susceptibility particularly in early disease, we conducted a preplanned case-control study to investigate the association between the BRM promoter variants and stage I/II upper aerodigestive tract (UADT) cancers (i.e., lung, esophageal, head and neck), a group of early-stage malignancies in which molecular and genetic etiologic factors are poorly understood. The effects of various clinical factors on this association were also studied. We analyzed 562 cases of early-stage UADT cancers and 993 matched healthy controls. The double homozygous BRM promoter variants were associated with a significantly increased risk of early stage UADT cancers (adjusted odds ratio [aOR], 2.46; 95% confidence interval [CI], 1.7-3.8). This association was observed in lung (aOR, 2.61; 95% CI, 1.5-4.9) and head and neck (aOR, 2.75; 95% CI, 1.4-5.6) cancers, but not significantly in esophageal cancer (aOR, 1.66; 95% CI, 0.7-5.8). There was a nonsignificant trend for increased risk in the heterozygotes or single homozygotes. The relationship between the BRM polymorphisms and early-stage UADT cancers was independent of age, sex, smoking status, histology, and clinical stage. These findings suggest that the BRM promoter double insertion homozygotes may be associated with an increased risk of early-stage UADT cancers independent of smoking status and histology, which must be further validated in other populations.
    Cancer medicine. 02/2014;
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    ABSTRACT: To correlate metabolic response to neoadjuvant chemoradiotherapy (NACR) on FDG-PET/CT using PERCIST-based criteria to pathologic and clinical response, and survival in patients with locally advanced esophageal cancer (LAEC). Forty-five patients with LAEC underwent PET/CT at baseline and after NACR. Tumors were evaluated using PERCIST (PET response criteria in solid tumors)-based criteria including SUL, SUL tumor/liver ratio, % change in SUL. These parameters were compared to pathology regression grade (PRG), clinical response (including residual or new disease beyond the surgical specimen), and overall survival. On surgical pathology, there was complete or near-complete regression of tumor in 51.1 %, partial response in 42.2 %, and lack regression in 4.4 %. One patient (2.2 %) had progression of disease on imaging and did not undergo surgical resection. None of the baseline PET parameters had significant correlation to pathology regression grade or clinical response. On follow-up, a positive correlation was found between post-therapy SUL ratio, %∆ SUL and %∆ SUL ratio and clinical response (p = 0.025, 0.035, 0.030, respectively). A weak correlation was found between post-therapy SUL ratio to PRG (p = 0.049). A strong correlation was found between the metabolic response score and PRG (p = 0.002) as well as between metabolic response and clinical response (p < 0.001). PERCIST-based metabolic response assessment to NACR in LAEC may correlate with clinical outcome and survival.
    Annals of Nuclear Medicine 01/2014; · 1.41 Impact Factor
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    ABSTRACT: Abiraterone acetate (abiraterone) prolongs overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC). This study's objective was to retrospectively identify factors associated with prostate-specific antigen (PSA) response to abiraterone and validate them in an independent cohort. We hypothesized that the neutrophil/lymphocyte ratio (NLR), thought to be an indirect manifestation of tumor-promoting inflammation, may be associated with response to abiraterone. All patients receiving abiraterone at the Princess Margaret (PM) Cancer Centre up to March 2013 were reviewed. The primary end point was confirmed PSA response defined as PSA decline ≥50% below baseline maintained for ≥3 weeks. Potential factors associated with PSA response were analyzed using univariate and multivariable analyses to generate a score, which was then evaluated in an independent cohort from Royal Marsden (RM) NHS foundation. A confirmed PSA response was observed in 44 out of 108 assessable patients (41%, 95% confidence interval 31%-50%). In univariate analysis, lower pre-abiraterone baseline levels of lactate dehydrogenase, an NLR ≤ 5 and restricted metastatic spread to either bone or lymph nodes were each associated with PSA response. In multivariable analysis, only low NLR and restricted metastatic spread remained statistically significant. A score derived as the sum of these two categorical variables was associated with response to abiraterone (P = 0.007). Logistic regression analysis on an independent validation cohort of 245 patients verified that this score was associated with response to abiraterone (P = 0.003). It was also associated with OS in an exploratory analysis. A composite score of baseline NLR and extent of metastatic spread is associated with PSA response to abiraterone and OS. Our data may help understand the role of systemic inflammation in mCRPC and warrant further research.
    Annals of Oncology 01/2014; · 7.38 Impact Factor
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    ABSTRACT: Background Biliary tract cancers (BTCs) include intrahepatic (IHC), hilar, distal bile duct (DBD) and gallbladder carcinoma (GBC). Neutrophil/lymphocyte ratio (NLR), a marker of host inflammation, is prognostic in several cancers but has not been reviewed in large BTC series, or advanced BTC (ABTC) at diagnosis. Patients and methods Baseline demographics and NLR at diagnosis were retrospectively evaluated in 864 consecutive patients with BTC treated from January 1987 to December 2012. The association between NLR and overall survival (OS) was determined using a multivariable Cox proportional hazards model. Results Eight hundred and sixty-four patients were included in the analysis, of which 62% had ABTC and 38% had surgery with curative intent. Median age was 65 years, 444 (51%) were male and 727 (84%) had performance status (PS) ⩽2. A NLR ⩾3.0, PS >2, IHC primary, stage, lack of surgery, haemoglobin <110 g/L and albumin <40 g/L were associated with significantly worse OS on multivariable analysis. A NLR ⩾3.0 was an independent prognostic factor for OS for the entire cohort; median OS was 21.6 months versus 12.0 months for patients with NLR <3.0 versus NLR ⩾3.0 respectively (adjusted hazard ratio (HR)-1.26, 95% confidence interval (CI); 1.06–1.50, P = 0.01). NLR was also prognostic in patients with ABTC (HR-1.26, 95% CI; 1.02–1.56, P = 0.035) and hilar cancer: overall group (N = 149) (HR-1.70, 95% CI; 1.10–2.50, P = 0.01) and advanced group (N = 111) (HR-1.57, 95% CI; 1.04–2.44, P = 0.048). Conclusion Baseline NLR is a readily available and inexpensive prognostic biomarker in patients with BTC and likely warrants validation in large prospective clinical trials.
    European journal of cancer (Oxford, England: 1990) 01/2014; · 4.12 Impact Factor
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    ABSTRACT: Targeted therapies in metastatic renal cell carcinoma (mRCC) have been approved based on registration clinical trials that have strict eligibility criteria. The clinical outcomes of patients treated with targeted agents but are ineligible for trials are unknown. mRCC patients treated with vascular endothelial growth factor-targeted therapy were retrospectively deemed ineligible for clinical trials (according to commonly used inclusion/exclusion criteria) if they had a Karnofsky performance status (KPS) <70%, nonclear-cell histology, brain metastases, hemoglobin ≤9 g/dl, creatinine >2× the upper limit of normal, corrected calcium ≥12 mg/dl, platelet count of <100 × 10(3)/uL, or neutrophil count <1500/mm(3). Overall, 768 of 2210 (35%) patients in the International Metastatic RCC Database Consortium (IMDC) were deemed ineligible for clinical trials by the above criteria. Between ineligible versus eligible patients, the response rate, median progression-free survival (PFS) and median overall survival of first-line targeted therapy were 22% versus 29% (P = 0.0005), 5.2 versus 8.6 months, and 12.5 versus 28.4 months (both P < 0.0001), respectively. Second-line PFS (if applicable) was 2.8 months in the trial ineligible versus 4.3 months in the trial eligible patients (P = 0.0039). When adjusted by the IMDC prognostic categories, the HR for death between trial ineligible and trial eligible patients was 1.55 (95% confidence interval 1.378-1.751, P < 0.0001). The number of patients that are ineligible for clinical trials is substantial and their outcomes are inferior. Specific trials addressing the unmet needs of protocol ineligible patients are warranted.
    Annals of Oncology 01/2014; 25(1):149-54. · 7.38 Impact Factor
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    ABSTRACT: Background Targeted therapy has become the mainstay of treatment for metastatic renal cell carcinoma (mRCC). The efficacy of this therapy in the older population is poorly understood. Patients and methods Data from patients with mRCC treated with first-line anti-VEGF therapy were collected through the International mRCC Database Consortium from 12 centers. Patient characteristics, data on second-line therapy, and outcomes, including treatment duration and overall survival, were evaluated using summary statistics and multivariate analysis. Results and limitations: 1,381 patients were treated with front-line targeted therapy; 144 (10%) were 75-years or older. 4% were favorable risk, 69% intermediate risk, and 27% poor risk as per Heng et al. JCO 2009 prognostic factors. The initial treatment for those ≥75-years was with sunitinib(n=98), sorafenib(n=35), bevacizumab(n=7), and AZD217(n=4). 23% of older patients and 39% of the younger patients went on to receive second-line therapy (p<0.0001). The overall response rate, median treatment duration and overall survival for the older vs. younger group were 18% vs. 25% (p=0.0975), 5.5months vs. 7.5months (p=0.1388) and 16.8months vs. 19.7months (p=0.3321), respectively. When adjusted for poor prognostic factors, age 75-years and above was not found to be associated with poorer overall survival (HR 1.002, 95%CI 0.781-1.285) or shorter treatment duration (HR 1.018, 95%CI 0.827-1.252). The retrospective study design was the primary limitation. Conclusions The use of advanced age as a selection criterion for targeted therapy requires further study, with data suggesting no clinically meaningful differences in overall response rate, treatment duration, and overall survival between older and younger age groups.
    Clinical Genitourinary Cancer 01/2014; · 1.43 Impact Factor
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    ABSTRACT: Background Approval of the mTOR inhibitors for the treatment of metastatic RCC was based on efficacy in poor risk patients in the first-line setting for temsirolimus and in VEGF inhibitor-refractory patients for everolimus. We strove to characterize temsirolimus and everolimus use and effectiveness in the first-line setting. Patients and Methods Retrospective database analysis of mRCC patients who received mTOR inhibitors as first-line targeted therapy. The Kaplan-Meier product-limit method was used to estimate the distributions of progression-free survival (PFS) and overall survival (OS). Results We identified 127 mRCC patients who had received a first-line mTOR inhibitor. Temsirolimus was administered in 73% and everolimus in 27%. The main reasons for choice of temsirolimus were poor risk disease (38%), non-clear cell histology (27%), and clinical trial availability (15%) whereas clinical trial (82%) and non-clear cell histology (6%) drove everolimus selection. Of the temsirolimus and everolimus patients, 58% and 32% were poor risk by IMDC criteria, respectively. The median PFS and OS were 3.4 and 12.5 months and 4.8 and 15.9 months with temsirolimus and everolimus respectively. While limited by small numbers, this study characterizes a real world, international experience with the use of mTOR inhibition in treatment-naïve metastatic RCC patients. Conclusions Poor-risk RCC, non-clear cell histology, and clinical trials were the predominant reasons for mTOR inhibitor selection in the front-line setting. Given the different patient populations in which they were administered, direct comparisons of the frontline efficacy of temsirolimus and everolimus cannot be made.
    Clinical Genitourinary Cancer 01/2014; · 1.43 Impact Factor
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    ABSTRACT: Multiple factors can influence outcomes of patients receiving identical interventions in clinical trials and in routine practice. Here, we compare outcomes of men with metastatic castrate-resistant prostate cancer (mCRPC) treated with docetaxel and prednisone in routine practice and in clinical trials. We reviewed patients with mCRPC treated with docetaxel at Princess Margaret Cancer Centre. Primary outcomes were overall survival and PSA response rate. Secondary outcomes were reasons for discontinuation and febrile neutropenia. Outcomes were compared for men treated in routine practice and in clinical trials, and with data from the TAX 327 study. From 2001 to 2011, 438 men were treated, of whom 357 received 3-weekly docetaxel as first-line chemotherapy: 314 in routine practice and 43 in clinical trials. Trial patients were younger and had better performance status. Median survival was 13.6 months [95% confidence interval (95% CI) 12.1-15.1 months] in routine practice and 20.4 months (95% CI 17.4-23.4 months, P = 0.007) within clinical trials, compared with 19.3 months (95% CI 17.6-21.3 months, P < 0.001) in the TAX 327 study. PSA response rates were 45%, 54%, and 53%, respectively (P = NS). Reasons for treatment discontinuation were similar although trial patients received more cycles (median: 6 versus 8 versus 9.5, P < 0.001). Rates of febrile neutropenia were 9.6, 0, and 3% (P < 0.001) while rates of death within 30 days of last dose were 4%, 0%, and 3%, respectively (P = NS). Survival of patients with mCRPC treated with docetaxel in routine practice is shorter than for men included in trials and is associated with more toxicity.
    Annals of Oncology 10/2013; · 7.38 Impact Factor
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    ABSTRACT: The skeleton and liver are frequently involved sites of metastasis in patients with metastatic renal cell carcinoma (RCC). To analyze outcomes based on the presence of bone metastases (BMs) and/or liver metastases (LMs) in patients with RCC treated with targeted therapy. We conducted a review from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) of 2027 patients with metastatic RCC. We analyzed the impact of the site of metastasis on overall survival (OS) and time-to-treatment failure. Statistical analyses were performed using multivariable Cox regression. The presence of BMs was 34% overall, and when stratified by IMDC risk groups was 27%, 33%, and 43% in the favorable-, intermediate-, and poor-risk groups, respectively (p<0.001). The presence of LMs was 19% overall and higher in the poor-risk patients (23%) compared with the favorable- or intermediate-risk groups (17%) (p=0.003). When patients were classified into four groups based on the presence of BMs and/or LMs, the hazard ratio, adjusted for IMDC risk factors, was 1.4 (95% confidence interval [CI], 1.22-1.62) for BMs, 1.42 (95% CI, 1.17-1.73) for LMs, and 1.82 (95% CI, 1.47-2.26) for both BMs and LMs compared with other metastatic sites (p<0.0001). The prediction model performance for OS was significantly improved when BMs and LMs were added to the IMDC prognostic model (likelihood ratio test p<0.0001). Data in this analysis were collected retrospectively. The presence of BMs and LMs in patients treated with targeted agents has a negative impact on survival. Patients with BMs and/or LMs may benefit from earlier inclusion on clinical trials of novel agents or combination-based therapies.
    European Urology 08/2013; · 10.48 Impact Factor
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    ABSTRACT: A subset of primarily localized renal cell carcinoma (RCC) patients will experience disease recurrence ≥5 yr after initial nephrectomy. To characterize the clinical outcome of patients with late recurrence beyond 5 yr. Patients with metastatic RCC (mRCC) treated with targeted therapy were retrospectively characterized according to time to relapse. Relapse was defined as the diagnosis of recurrent metastatic disease >3 mo after initial curative-intent nephrectomy. Patients with synchronous metastatic disease at presentation were excluded. Patients were classified as early relapsers (ERs) if they recurred within 5 yr; late relapsers (LRs) recurred after 5 yr. Demographics were compared with the Student t test, the chi-square test, or the Fisher exact test. The survival time was estimated with the Kaplan-Meier method, and associations with survival outcome were assessed with univariable and multivariable Cox regression analyses. Among 1210 mRCC patients treated with targeted therapy after surgery for localized disease, 897 (74%) relapsed within the first 5 yr and 313 (26%) (range: 5-35 yr) after 5 yr. LRs presented with younger age (p<0.0001), fewer with sarcomatoid features (p<0.0001), more clear cell histology (p=0.001), and lower Fuhrman grade (p<0.0001). Overall objective response rates to targeted therapy were better in LRs versus ERs (31.8% vs 26.5%; p=0.004). LRs had significantly longer progression-free survival (10.7 mo vs 8.5 mo; p=0.005) and overall survival (OS; 34.0 mo vs 27.4 mo; p=0.004). The study is limited by its retrospective design, noncentralized imaging and pathology review, missing information on metastatectomy, and nonstandardized follow-up protocols. A quarter of patients who eventually developed metastatic disease and were treated with targeted therapy relapsed over 5 yr from initial nephrectomy. LRs have more favorable prognostic features and consequently better treatment response and OS.
    European Urology 07/2013; · 10.48 Impact Factor
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    ABSTRACT: There are high rates of recurrence after definitive surgery in biliary tract cancer patients. We reviewed the use and effectiveness of adjuvant therapy (AT; chemotherapy±radiotherapy) in a single institution series. Characteristics, treatment details, and follow-up data of all patients with biliary tract cancer who had definitive surgery from January 1987 to September 2011 were reviewed. The association between baseline variables and disease-free survival/overall survival (OS) were tested using Cox proportional hazard analysis in the univariable and multivariable settings. Analysis included 296 patients (58% male; median age, 63 y). Negative or microscopically positive resections were reported in 42% and 14%, respectively, with 44% not reported. Node positivity was reported in 35% patients. AT was given in 28% of patients with 59% receiving chemotherapy and 35% concurrent chemotherapy/radiotherapy. Disease recurred in 60% patients. AT was associated with significantly improved OS (hazard ratio, 0.41; P=0.02). Compared with R0 resection, patients with R1 resection derived significantly increased benefit from AT (P for difference 0.02). In the node positive population (n=103), AT was associated with significantly improved OS (hazard ratio, 0.60; 95% confidence interval, 0.38-0.95; P=0.03). Patients with R1 resection and node positive disease receiving AT after definitive surgery seem to derive OS advantage. Large prospective trials are needed to confirm these data.
    American journal of clinical oncology 07/2013; · 2.21 Impact Factor
  • Canadian Urological Association journal = Journal de l'Association des urologues du Canada 07/2013; 7(7-8):238-43. · 1.66 Impact Factor
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    ABSTRACT: BACKGROUND: This study aimed to apply the International mRCC Database Consortium (IMDC) prognostic model in metastatic non-clear cell renal cell carcinoma (nccRCC). In addition, the survival outcome of metastatic nccRCC patients was characterized. METHODS: Data on 2215 patients (1963 with clear-cell RCC [ccRCC] and 252 with nccRCC) treated with first-line VEGF- and mTOR-targeted therapies were collected from the IMDC. Time to treatment failure (TTF) and overall survival (OS) were compared in groups with favorable, intermediate, and poor prognoses according to IMDC prognostic criteria RESULTS: The median OS of the entire cohort was 20.9 months. nccRCC patients were younger (P < .0001) and more often presented with low hemoglobin (P = .014) and elevated neutrophils (P = .0001), but otherwise had clinicopathological features similar to those of ccRCC patients. OS (12.8 vs 22.3 months; P < .0001) and TTF (4.2 vs 7.8 months; P < .0001) were worse in nccRCC patients compared with ccRCC patients. The hazard ratio for death and TTF when adjusted for the prognostic factors was 1.41 (95% CI, 1.19-1.67; P < .0001) and 1.54 (95% CI, 1.33-1.79; P < .0001), respectively. The IMDC prognostic model reliably discriminated 3 risk groups to predict OS and TTF in nccRCC; the median OS of the favorable, intermediate, and poor prognosis groups was 31.4, 16.1, and 5.1 months, respectively (P < .0001), and the median TTF was 9.6, 4.9, and 2.1 months, respectively (P < .0001). CONCLUSIONS: Although targeted agents have significantly improved the outcome of patients with nccRCC, for the majority survival is still inferior compared with patients with ccRCC. The IMDC prognostic model reliably predicts OS and TTF in nccRCC and ccRCC patients. Cancer 2013. © 2013 American Cancer Society.
    Cancer 05/2013; · 5.20 Impact Factor
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    ABSTRACT: BACKGROUND: The outcomes and prognosis of patients with brain metastases from advanced renal cell carcinoma (RCC) are not well characterized in the targeted-therapy era. METHODS: Data from patients with metastatic RCC (mRCC) and brain metastases treated with targeted therapy were collected through the International Metastatic Renal Cell Carcinoma Database Consortium from 7 cancer centers. RESULTS: Overall, 106 (15%) of 705 patients with mRCC had brain metastases. Forty-seven patients had brain metastases at the start of first-line anti-vascular endothelial growth factor therapy, and the rest developed metastases during follow-up. Of the patients with brain metastases, 12%, 42% and 29% were in the favorable, intermediate, and poor prognosis groups, respectively, per the Heng criteria. Ninety percent had cerebral metastases, 17% had cerebellar metastases, 37% had a Karnofsky performance status (KPS) <80%, and 80% had neurologic symptoms at presentation. The median largest size and number of brain metastases was 1.8 cm (range, 0.2-6.6 cm) and one (range, 1 to innumerable), respectively. The patients were treated with sunitinib (n = 77), sorafenib (n = 23), bevacizumab (n = 5), and temsirolimus (n = 1). Local disease treatment included whole brain radiotherapy (81%), stereotactic radiosurgery (25%), and neurosurgery (25%). On multivariable analysis, KPS < 80%, diagnosis to treatment with targeted therapy <1 year, and a higher number of brain metastases (>4) was associated with worse survival from the time of diagnosis with brain metastases. CONCLUSIONS: Patients with brain metastases from RCC are unlikely to be in the favorable risk group. KPS at the start of therapy, diagnosis to treatment time, and the number of brain metastases are prognostic factors for overall survival.
    Clinical Genitourinary Cancer 05/2013; · 1.43 Impact Factor
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    ABSTRACT: BACKGROUND: The central goal of cancer care is to improve patient outcomes through advancing medical knowledge. Therefore, participation in clinical trials is encouraged to demonstrate efficacy and understand toxicities of medical interventions. In the oncology setting, these interventions are also frequently accompanied by clinical care to maintain bone health throughout the course of disease. In this study we examined the use of a study screener to enhance accrual and highlight bone health issues in a tertiary referral cancer center. PATIENTS AND METHODS: A study screener was introduced into 4 separate genitourinary clinics in a tertiary referral cancer center. Over a retrospective and subsequent prospective 10-week period, clinical trial accrual and bone health parameters were measured. RESULTS: There were no statistically significant differences between the retrospective and prospective periods in probability of approaching a patient for clinical trials (P = .60), accrual rates (P = .80), or proportion of patients later found ineligible (P = .31). The difference in initiation of calcium and vitamin D between the retrospective and prospective patients was statistically significant (P < .0001) and the difference between cohorts for starting treatment with zoledronic acid or denosumab was statistically significant (P = .02) and approached significance for the prostate cancer patients (P = .12). CONCLUSION: This pilot study suggests that in an academic setting, there is appropriate physician awareness of clinical trial availability, however the use of medication to improve bone health is suboptimal, and requires further research to identify and remove barriers to appropriate use including additional evidence of beneficial toxicity-benefit and cost-benefit ratios.
    Clinical Genitourinary Cancer 05/2013; · 1.43 Impact Factor
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    ABSTRACT: PURPOSE OF REVIEW: Gallbladder carcinoma (GBC), classified as a biliary tract cancer (BTC) along with intrahepatic and extrahepatic cholangiocarcinomas, is a rare disease in Western countries, but a highly prevalent disease in Chile, other countries in Latin America, India and Japan. It commonly presents at an advanced stage, and has limited therapeutic options. Cisplatin/gemcitabine has emerged as the first-line standard of care for patients with advanced BTCs, but the prognosis remains poor. Development of molecularly targeted therapies in advanced BTC remains challenging. RECENT FINDINGS: Comprehension of the molecular events in gallbladder carcinogenesis may provide a novel targeted therapeutic approach, and early stage clinical trials with targeted therapies appear promising, although the relationship between subsets of patients with positive responses to therapy and tumor genetics requires further exploration. Recent developments in targeted therapeutics, directed against several key signalling pathways in BTC, including epidermal growth factor receptor, angiogenesis, and the mitogen-activated protein kinase pathway will be discussed, in addition to the potential application of prognostic factors and markers. SUMMARY: The future therapeutic spectrum for BTC and GBC will likely encompass novel combinations of targeted therapies with cytostatics in scientifically and molecularly directed schedules, thus permitting fewer mechanisms of escape for tumor cells.
    Current opinion in oncology 04/2013; · 4.09 Impact Factor
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    ABSTRACT: PURPOSETo describe outcomes of prospective trials of stereotactic body radiotherapy (SBRT) for hepatocellular carcinoma (HCC).Patients And methodsTwo trials of SBRT for patients with active HCC unsuitable for standard locoregional therapies were conducted from 2004 to 2010. All patients had Child-Turcotte-Pugh class A disease, with at least 700 mL of non-HCC liver. The SBRT dose range was 24 to 54 Gy in six fractions. Primary end points were toxicity and local control at 1 year (LC1y), defined as no progressive disease (PD) of irradiated HCC by RECIST (Response Evaluation Criteria in Solid Tumors). RESULTS: n = 50; Trial 2, 2007 to 2010: n = 52). Underlying liver disease was hepatitis B in 38% of patients, hepatitis C in 38%, alcohol related in 25%, other in 14%, and none in 7%. Fifty-two percent received prior therapies (no prior sorafenib). TNM stage was III in 66%, and 61% had multiple lesions. Median gross tumor volume was 117.0 mL (range, 1.3 to 1,913.4 mL). Tumor vascular thrombosis (TVT) was present in 55%, and extrahepatic disease was present in 12%. LC1y was 87% (95% CI, 78% to 93%). SBRT dose (hazard ratio [HR] = 0.96; P = .02) and being in Trial 2 (HR = 0.38; P = .03) were associated with LC1y on univariate analysis. Toxicity ≥ grade 3 was seen in 30% of patients. In seven patients (two with TVT PD), death was possibly related to treatment (1.1 to 7.7 months after SBRT). Median overall survival was 17.0 months (95% CI, 10.4 to 21.3 months), for which only TVT (HR = 2.47; P = .01) and being in Trial 2 (HR = 0.49; P = .01) were significant on multivariate analysis. CONCLUSION These results provide strong rationale for studying SBRT for HCC in a randomized trial.
    Journal of Clinical Oncology 04/2013; · 18.04 Impact Factor
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    ABSTRACT: Background:Elderly patients tend to be underrepresented in renal cell carcinoma (RCC) clinical trials. The Sorafenib RCC Integrated Database includes data from six clinical trials and two expanded-access studies evaluating sorafenib monotherapy in >4600 patients with RCC. Using this database, sorafenib tolerability and treatment patterns were analysed according to age group (<55, 55-<65, 65-<75, or 75 years).Methods:Dosing patterns, and incidence, prevalence and cumulative incidence of drug-related adverse events (DRAEs) and fatal DRAEs were assessed.Results:Overall, 4684 patients were evaluable (<55 years, n=1126; 55-<65, n=1579; 65-<75, n=1382; 75, n=559). Treatment patterns were generally similar across subgroups, although sorafenib treatment duration was ∼30% shorter in the 75-years subgroup. There were no substantial differences in any-grade DRAEs with sorafenib between subgroups. Drug-related adverse events and dose modifications due to DRAEs tended to occur in months 0-3 and declined thereafter; there was no evidence of cumulative toxicity. Fatal DRAEs were rare (0.7% overall; 95% confidence interval, 0.5-1.0%).Conclusion:Sorafenib was well tolerated regardless of age in a heterogeneous population of RCC patients.British Journal of Cancer advance online publication, 15 January 2013; doi:10.1038/bjc.2012.543 www.bjcancer.com.
    British Journal of Cancer 01/2013; · 5.08 Impact Factor
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    ABSTRACT: There are many active drugs to treat metastatic renal cell carcinoma (mRCC) patients who progress through their first-line vascular endothelial growth factor (VEGF) inhibitor. Many clinicians choose a second-line VEGF inhibitor based on the type of response to first-line VEGF inhibitor, without data supporting this practice. This study was conducted to determine the association of response to second-line VEGF inhibitor with response to first-line VEGF inhibitor. All mRCC patients in participating centers of the International mRCC Database Consortium who were treated from January 2004 through June 2011 with a second-line VEGF inhibitor after failure of a different first-line VEGF inhibitor were retrospectively identified. The primary outcome is objective response rate (ORR) and the secondary outcome is progression-free survival (PFS) in each line of therapy. Of 1,602 total database patients, 464 patients received a first- and second-line VEGF inhibitor. The ORR to first-line therapy was 22 %, and the ORR to second-line therapy was 11 %. The ORR to second-line therapy was not different among patients achieving partial response versus stable disease versus progressive disease to first-line therapy (14 % vs. 10 % vs. 11 %, respectively; chi-squared trend test p = 0.17). The median PFS on first-line VEGF-targeted therapy was 7.5 months (95 % CI, 6.6-8.1), and the median PFS on second-line VEGF inhibitor was 3.9 months (95 % CI, 3.6-4.5). There was no correlation between first-line and second-line PFS (Pearson correlation coefficient 0.025; p = 0.59). The clinical response to a second-line VEGF inhibitor is not dependent on response to the first-line VEGF-inhibitor. Further studies are needed to define clinical parameters that predict response to second-line therapy to optimize the sequence of VEGF-targeted therapy in metastatic RCC patients.
    Targeted Oncology 01/2013; · 2.76 Impact Factor

Publication Stats

1k Citations
471.73 Total Impact Points

Institutions

  • 2004–2014
    • The Princess Margaret Hospital
      Toronto, Ontario, Canada
  • 2010–2013
    • Dana-Farber Cancer Institute
      • Department of Medical Oncology
      Boston, MA, United States
  • 2009–2013
    • Tom Baker Cancer Centre
      Calgary, Alberta, Canada
  • 2012
    • Stanford University
      • Stanford Cancer Institute
      Stanford, CA, United States
  • 2004–2012
    • University of Toronto
      • • Department of Surgery
      • • Department of Radiation Oncology
      Toronto, Ontario, Canada
  • 2011
    • The University of Calgary
      Calgary, Alberta, Canada
    • London Health Sciences Centre
      London, Ontario, Canada
    • Vancouver Prostate Centre
      Vancouver, British Columbia, Canada
  • 2005–2009
    • University Health Network
      Toronto, Ontario, Canada
  • 2007
    • Hospital Israelita Albert Einstein
      San Paulo, São Paulo, Brazil
  • 2006
    • Dalhousie University
      Halifax, Nova Scotia, Canada