Jennifer J Knox

The Princess Margaret Hospital, Toronto, Ontario, Canada

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Publications (137)803.59 Total impact

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    ABSTRACT: Polymorphisms in the VEGF/angiogenesis pathway have been previously implicated in cancer risk, prognosis, and response to therapy including in esophageal adenocarcinoma. Prior esophageal adenocarcinoma studies focused on using candidate polymorphisms, limiting the discovery of novel polymorphisms. Here, we applied the tagSNP approach to identify new VEGF-pathway polymorphisms associated with esophageal adenocarcinoma prognosis and validated them in an independent cohort of esophageal adenocarcinoma patients. In 231 esophageal adenocarcinoma patients of all stages/treatment plans, 58 genetic polymorphisms (18 KDR, 7 VEGFA, 33 FLT1), selected through tagging and assessment of predicted function were genotyped. Cox-proportional hazard models adjusted for important socio-demographic and clinico-pathological factors were applied to assess the association of genetic polymorphisms with overall survival (OS) and progression-free survival (PFS). Significantly associated polymorphisms were then validated in an independent cohort of 137 esophageal adenocarcinoma patients. Among the 231 discovery cohort patients, 86% were male, median diagnosis age was 64 years, 34% were metastatic at diagnosis, and median OS and PFS were 20 and 12 months respectively. KDR rs17709898 was found significantly associated with PFS (adjusted hazard ratio,aHR=0.69, 95%CI:0.53-0.90;P=5.2E-3). FLT1 rs3794405 and rs678714 were significantly associated with OS (aHR=1.44, 95%CI:1.04-1.99;P=0.03 and aHR=1.50, 95%CI:1.01- 2.24;P=0.04, respectively). No VEGFA polymorphisms were found significantly associated with either outcome. Upon validation, FLT1 rs3794405 remained strongly associated with OS (aHR=1.59, 95%CI:1.04-2.44;P=0.03). FLT1 rs3794405 is significantly associated with OS in esophageal adenocarcinoma; whereby each variant allele confers a 45-60% increased risk in mortality. Validation and evaluation of this association in other cancer sites is warranted.
    Carcinogenesis 05/2015; DOI:10.1093/carcin/bgv073 · 5.27 Impact Factor
  • Jennifer J Knox, Sean P Cleary, Laura A Dawson
    Journal of Clinical Oncology 04/2015; 33(16). DOI:10.1200/JCO.2014.60.1153 · 17.88 Impact Factor
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    ABSTRACT: AGS-003 is an autologous immunotherapy prepared from fully matured and optimized monocyte-derived dendritic cells, which are co-electroporated with amplified tumor RNA plus synthetic CD40L RNA. AGS-003 was evaluated in combination with sunitinib in an open label phase 2 study in intermediate and poor risk, treatment naïve patients with metastatic clear cell renal cell carcinoma (mRCC). Twenty-one intermediate and poor risk patients were treated continuously with sunitinib (4 weeks on, 2 weeks off per 6 week cycle). After completion of the first cycle of sunitinib, patients were treated with AGS-003 every 3 weeks for 5 doses, then every 12 weeks until progression or end of study. The primary endpoint was to determine the complete response rate. Secondary endpoints included clinical benefit, safety, progression free survival (PFS) and overall survival (OS). Immunologic response was also monitored. Thirteen patients (62%) experienced clinical benefit (9 partial responses, 4 with stable disease); however there were no complete responses in this group of intermediate and poor risk mRCC patients and enrollment was terminated early. Median PFS from registration was 11.2 months (95% CI 6.0, 19.4) and the median OS from registration was 30.2 months (95% CI 9.4, 57.1) for all patients. Seven (33%) patients survived for at least 4.5 years, while five (24%) survived for more than 5 years, including 2 patients who remain progression-free with durable responses for more than 5 years at the time of this report. AGS-003 was well tolerated with only mild injection-site reactions. The most common adverse events were related to expected toxicity from sunitinib therapy. In patients who had sequential samples available for immune monitoring, the magnitude of the increase in the absolute number of CD8(+) CD28(+) CD45RA(-) effector/memory T cells (CTLs) after 5 doses of AGS-003 relative to baseline, correlated with overall survival. AGS-003 in combination with sunitinib was well tolerated and yielded supportive immunologic responses coupled with extension of median and long-term survival in an unselected, intermediate and poor risk prognosis mRCC population. #NCT00678119.
    04/2015; 3(1):14. DOI:10.1186/s40425-015-0055-3
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    ABSTRACT: Previous prognostic models for second-line systemic therapy in patients with metastatic renal cell carcinoma have not been studied in the setting of targeted therapy. We sought to validate the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model in patients with metastatic renal cell carcinoma receiving next-line targeted therapy after progression on first-line targeted therapy. In this population-based study, we analysed patients who received second-line targeted therapy for metastatic renal cell carcinoma at 19 centres in Canada, USA, Greece, Japan, Singapore, South Korea, and Denmark. The primary endpoint was overall survival since the initiation of second-line therapy. We compared the prognostic performance of the IMDC model with the three-factor MSKCC model used for previously treated patients for overall survival since the start of second-line targeted therapy. Between Jan 1, 2005, and Nov 30, 2012, we included 1021 patients treated with second-line targeted therapy. Median overall survival since the start of second-line targeted therapy was 12·5 months (95% CI 11·3-14·3). Five of six predefined factors in the IMDC model (anaemia, thrombocytosis, neutrophilia, Karnofsky performance status [KPS] <80, and <1 year from diagnosis to first-line targeted therapy) were independent predictors of poor overall survival on multivariable analysis. The concordance index using all six prognostic factors (ie, also including hypercalcaemia) was 0·70 (95% CI 0·67-0·72) with the IMDC model and was 0·66 (95% CI 0·64-0·68) with the three-factor MSKCC model. When patients were divided into three risk categories using IMDC criteria, median overall survival was 35·3 months (95% CI 28·3-47·8) in the favourable risk group (n=76), 16·6 months (14·9-17·9) in the intermediate risk group (n=529), and 5·4 months (4·7-6·8) in the poor risk group (n=261). The IMDC prognostic model can be applied to patients previously treated with targeted therapy, in addition to previously validated populations in first-line targeted therapy. The IMDC prognostic model in the second-line targeted therapy setting has an improved prognostic performance and is applicable to a more contemporary patient cohort than that of the three-factor MSKCC model. DF/HCC Kidney Cancer SPORE P50 CA101942-01, Kidney Cancer Research Network of Canada, Canadian Institute for Health Research, Trust Family, Loker Pinard, Michael Brigham, and Gerald DeWulf. Copyright © 2015 Elsevier Ltd. All rights reserved.
    The Lancet Oncology 02/2015; 16(3). DOI:10.1016/S1470-2045(14)71222-7 · 24.73 Impact Factor
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    ABSTRACT: Cisplatin-based neoadjuvant chemotherapy (NC) improves overall survival in muscle-invasive bladder cancer (MIBC), but there are currently no predictive biomarkers of response to NC in MIBC. An increased peripheral blood neutrophil to lymphocyte ratio (NLR) is a marker of systemic inflammation and is linked to poor prognosis in some solid tumors. We evaluated whether NLR is associated with pathological response (pathR) in MIBC patients who receive NC. MIBC patients treated with NC and radical cystectomy (RC) between July 2006 and April 2013 were retrospectively reviewed. The primary end point was to find variables associated with pathR in the RC specimen after NC. Potential predictive markers were analyzed using logistic regression. NLR values before NC, midway through NC, and before RC were collected and compared between patients who achieved pathR ('responders') and those who did not ('nonresponders'). In 26 evaluable patients, age, sex, performance status, smoking status, stage, hydronephrosis, NLR before NC, midway through NC, and before RC were not significantly associated with pathR, but the pattern of NLR change between responders and nonresponders was significantly different (P = .038). Responders exhibited a sustained decrease in NLR during NC until RC, and nonresponders exhibited a transient decrease in NLR which then increased to above its baseline before RC. The pattern of change in NLR during NC varied significantly between responders and nonresponders. We hypothesize that a sustained decrease in inflammatory burden during NC is associated with pathR. Despite limitations of a small retrospective study, our observations might have clinical implications and warrant further basic and clinical research. Copyright © 2015 Elsevier Inc. All rights reserved.
    Clinical Genitourinary Cancer 02/2015; DOI:10.1016/j.clgc.2015.02.001 · 1.69 Impact Factor
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    ABSTRACT: BACKGROUND Second-line treatment options in advanced hepatocellular carcinoma (HCC) are limited. Axitinib, a selective potent tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor VEGF) receptors 1, 2, and 3, merits exploration in HCC.METHODS This was a single-arm phase II trial of axitinib in advanced HCC. Eligible patients were Child-Pugh A/B7, with measurable progressive disease after TKIs/antiangiogenic drugs. Axitinib was started at 5 mg twice daily orally, titrated from 2 to 10 mg twice daily as tolerated. The primary end point was tumor control at 16 weeks by RECIST1.1; secondary end points were response rate, comparing response by RECIST1.1 to Choi and modified RECIST, exploring dynamic contrast-enhanced imaging models, safety, progression-free (PFS), and overall survival (OS).RESULTSThirty patients were treated. Of 26 patients evaluable for response, there were 3 partial responses (PR) per RECIST1.1; 13 PR by Choi, 6 PR and 1 complete response by modified RECIST. Tumor control rate at 16 weeks was 42.3%. Two-week perfusion changes were noted on functional imaging. Of 21 patients with evaluable α-fetoprotein response, 43% had >50% decrease from baseline. Most common axitinib-related grade 3/4 adverse events (AEs) were hypertension, thrombocytopenia and diarrhea. Of 11 patients with any grade hypertension, 7 had disease control >36wks. Four patients discontinued treatment due to AEs. Median PFS was 3.6months. Median OS was 7.1months.CONCLUSIONS With 42.3% tumor control at 16weeks, primary endpoint was met. Axitinib has shown encouraging tolerable clinical activity in VEGF-pretreated HCC patients but further study should be in a selected population incorporating potential biomarkers of response. Cancer 2015. © 2015 American Cancer Society.
    Cancer 01/2015; 121(10). DOI:10.1002/cncr.29227 · 4.90 Impact Factor
  • Jennifer J Knox
    Journal of Clinical Oncology 12/2014; 33(6). DOI:10.1200/JCO.2014.59.0521 · 17.88 Impact Factor
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    ABSTRACT: It is unknown whether lymph node metastases (LNM) and their localization negatively affect clinical outcome in metastatic renal cell carcinoma (mRCC) patients. To evaluate the clinicopathological features, survival outcome, and treatment response in mRCC patients with LNM versus those without LNM after treatment with targeted therapies (TT). Patients (n=2996) were first analyzed without consideration of lymph node (LN) localization or histologic subtype. Additional analyses (n=1536) were performed in subgroups of patients with supradiaphragmatic (SPD) LNM, subdiaphragmatic (SBD) LNM, and patients with LNM in both locations (SPD+/SBD+) without histologic considerations, and then separately in clear cell RCC (ccRCC) and non-clear cell RCC (nccRCC) patients, respectively. The primary outcome was overall survival (OS) and the secondary outcome was progression-free survival (PFS). All patients with LNM had worse PFS (p=0.001) and OS (p<0.001) compared to those without LNM. Compared to patients without LNM (PFS 8.8 mo; OS 25.1 mo), any SBD LNM involvement was associated with worse PFS (SBD, 6.8 mo; p=0.003; SPD+/SBD+, 5.5 mo; p<0.001) and OS (SBD, 16.2 mo; p<0.001; SPD+/SBD+, 11.5 mo; p<0.001). Both SBD and SPD+/SBD+ LNM were retained as independent prognostic factors in multivariate analyses (MVA) for PFS (p=0.006 and p=0.022, respectively) and OS (both p<0.001), while SPD LNM was not an independent risk factor. Likewise, in ccRCC, SBD LNM (19.8 mo) and SPD+/SBD+ LNM (12.85 mo) patients had the worst OS. SPD+/SBD+ LNM (p=0.006) and SBD LNM (p=0.028) were independent prognostic factors for OS in MVA, while SPD LNM was not significant (p=0.301). The study is limited by its retrospective design and the lack of pathologic evaluation of LNM in all cases. The metastatic spread of RCC to SBD lymph nodes is associated with poor prognosis in mRCC patients treated with TT. The presence of lymph node metastases below the diaphragm is associated with shorter survival outcome when metastatic renal cell carcinoma (mRCC) patients are treated with targeted therapies. Clinical trials should evaluate whether surgical removal of regional lymph nodes at the time of nephrectomy may improve outcomes in high-risk RCC patients. Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
    European Urology Supplements 12/2014; 14(2). DOI:10.1016/j.eururo.2014.11.054 · 3.37 Impact Factor
  • Cancer Research 11/2014; 73(8 Supplement):2562-2562. DOI:10.1158/1538-7445.AM2013-2562 · 9.28 Impact Factor
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    ABSTRACT: Background There is strong rationale to combine temsirolimus (TEM) with Bevacizumab (BEV) for patients with advanced HCC. Methods A modified two-stage Simon phase II trial was performed with plans to advance to stage 2 if more than 2 patients had confirmed PR or >18 patients were progression free at 6 months out of 25 in stage 1. Toxicity, PFS and overall survival were secondary endpoints. Eligible pts had advanced HCC, Child Pugh A liver status and no prior systemic therapy involving the VEGF or m-TOR targeted agents. Patients were treated with temsirolimus 25 mg IV on Days 1, 8, 15, and 22 of a 28 day cycle and bevacizumab 10 mg/kg IV on Days 1 and 15 of the cycle. Results Twenty-eight eligible patients were enrolled, 26 evaluable receiving a median of 6.5 cycles (range 1-18). Drug related toxicities were common including cytopenias, fatigue, mucositis, diarrhea and mild bleeds. Dose reductions or discontinuation of TEM were common. Accrual closed for presumed futility after interim analysis of the first 25 evaluable patients showed only one PR and 16/25 were progression-free at 6 months. However, the final data update in March 2013 demonstrated 4 confirmed PRs, a 5th unconfirmed PR and 16 /26 progression-free at 6 months. Median PFS and OS were 7 and 14 months respectively. Conclusion This first-line HCC trial evaluating the BEV/TEM doublet reports an ORR of 19 % and OS of 14 months which is favorable but requires further study at a more optimized dose and schedule.
    Investigational New Drugs 10/2014; 33(1). DOI:10.1007/s10637-014-0169-3 · 2.93 Impact Factor
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    ABSTRACT: Objective To assess the efficacy and toxicity of abiraterone and docetaxel in men with metastatic castration-resistant prostate cancer (mCRPC) of age > 80 compared to younger men. Methods Retrospective chart review of 116 men treated with abiraterone and 378 men treated with docetaxel at Princess Margaret Cancer Centre. Categorical outcome measures including PSA response rate (PSA-RR) and incidence of toxic side-effects were compared using Fisher's exact test. Overall survival (OS) and biochemical progression free survival (bPFS) were analyzed using the Kaplan–Meier method and log-rank tests. Results Thirty-four (29%) and 50 (13%) of the men treated with abiraterone or docetaxel, respectively, were octogenarians. For abiraterone there were no significant differences in PSA-RR (42% vs. 39%), bPFS (4.7 vs. 4.4 months) or OS (14.0 vs 20.7 months) between octogenarians and younger men, respectively. Toxicity was mild with no significant differences between age groups. For men treated with docetaxel PSA-RR and OS did not differ between age groups (40% vs. 45% and 12.0 vs. 14.1 months, respectively). However, rates of febrile neutropenia were 16% and 7% for octogenarians and younger men, respectively (p = 0.048). This difference was observed despite greater use of lower dose intensity and weekly docetaxel in the elderly cohort, with 20% of them receiving lower than standard dose during their first cycle compared to 7% of younger men (p = 0.004). Conclusions Treatment outcome on abiraterone and docetaxel did not differ in patients over and under the age of 80, but febrile neutropenia was more common in octogenarians treated with docetaxel despite lower dose intensity.
    Journal of Geriatric Oncology 10/2014; 6(1). DOI:10.1016/j.jgo.2014.09.183 · 1.15 Impact Factor
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    ABSTRACT: Background Targeted therapies improve survival in metastatic renal cell carcinoma (mRCC). However, survival patterns can be divergent and patients at the two extremes of the survival spectrum need to be characterized. Patients and Methods Data from 2161 patients included in the International mRCC Database Consortium (IMDC) were analyzed. We identified patients based on their duration of survival. Long-term survivors (LTS) were defined as overall survival (OS) ≥ 4 years and short-term survivors (STS) were patients with OS ≤ 6 months from the start of targeted therapy. Baseline characteristics including demographic, clinico-pathologic, and laboratory data were compared between LTS and STS. Treatment response by the RECIST criteria was summarized for the two survival groups. Results 152 patients were LTS and 218 were STS. Adverse clinical and laboratory prognostic factors previously described in the IMDC prognostic model were significantly more frequent in the STS group (p<0.0001). In the LTS group, 138 patients (91%) had non-progressive disease (non-PD) as best response to first-line targeted therapy, and 56 of 94 patients (60%) who received second-line therapy had non-PD. In the STS group, only 51 patients (23%) had non-PD on first-line therapy. None of 21 the patients who received second-line therapy had non-PD as best response. In LTS, the median duration of therapy was 23.6 months (range: 0.4, 81.8+) for first-line and 11.5 months (range: 0.6-45.7) for second-line compared to 2.0 and 0.8 months for the STS respectively. Conclusion Baseline prognostic criteria and absence of PD after first and second-line targeted therapy may characterize long-term survivors.
    Clinical Genitourinary Cancer 10/2014; 13(2). DOI:10.1016/j.clgc.2014.09.003 · 1.69 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 10/2014; 12(5). DOI:10.1016/j.clgc.2014.02.009 · 1.69 Impact Factor
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    ABSTRACT: BACKGROUND Abiraterone acetate (AA), oral CYP17 inhibitor, is an active agent in the treatment of metastatic castrate-resistant prostate cancer (mCRPC).METHODS We (R.L.A and N.A) retrospectively evaluated outcome in 12 men who were re-treated with AA following prior treatment with AA at the Princess Margaret Cancer Centre.RESULTSAll men were heavily pre-treated for mCRPC with a median of four prior lines of therapy, one of which was AA (given either pre- or post-chemotherapy). Eleven out of 12 (92%) men stopped their first treatment course of AA due to progression and one stopped for financial reasons. Seven men had a PSA decrease ≥50% following their first AA treatment, of which three (46%) had a PSA decrease ≥50% to AA re-treatment. The responses to AA re-treatment were generally short-lived with a median biochemical progression-free survival of 2.3 months and median treatment duration of 3.2 months. No PSA responses to AA re-treatment were seen in five men who did not have an initial PSA response to AA.CONCLUSIONS Our data suggest that AA re-challenge may have limited benefit in select men with mCRPC, and warrants further formal research. Prostate © 2014 Wiley Periodicals, Inc.
    The Prostate 10/2014; 74(14). DOI:10.1002/pros.22861 · 3.57 Impact Factor
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    ABSTRACT: Outcomes and prognosis of metastatic sarcomatoid renal cell carcinoma (sRCC) in the targeted-therapy era are not well described. This retrospective series of 230 patients with metastatic sRCC examined the role anti-VEGF agents as a treatment option. The validity of the IMDC prognostic model in patients with metastatic sRCC was confirmed. Sarcomatoid histology was found to be an independent factor for adverse prognosis. Background Sarcomatoid RCC (sRCC) is associated with poor prognosis. Data regarding outcome in the targeted therapy era is lacking. Methods Clinical, prognostic, and treatment parameters in mRCC patients with and without sarcomatoid histology treated with targeted therapy were retrospectively analyzed. Results 2,286 patients were identified (sRCC (n=230); non-sRCC (n=2,056)). sRCC patients had significantly worse IMDC prognostic criteria compared to non-sRCC (11% vs. 19% favorable risk, 49% vs. 57% intermediate risk, and 40% vs. 24% poor risk; p<0.0001). Time from original diagnosis to relapse (excluding synchronous metastatic disease) was shorter in the sRCC group (18.8 vs. 42.9 months; p<0.0001). There was no significant difference in the incidence of CNS metastases (6-8%) or underlying clear cell histology (87-88%). Greater than 93% of patients received VEGF inhibitors as first line therapy; objective response was less common in sRCC whereas primary refractory disease was more common (21% vs. 26% and 43% vs. 21%; p<0.0001, for both). sRCC patients had significantly less use of second- (p=0.018) and third-line (p<0.0001) systemic therapy. The median PFS / OS was 4.5 / 10.4 months in sRCC patients and 7.8 / 22.5 months in non-sRCC patients (p<0.0001 for both). Sarcomatoid histology was associated with a significantly worse PFS and OS after adjusting for individual IMDC risk factors in multivariable analysis (HR 1.5, p<0.0001 for both). Conclusions Patients with sRCC have a shorter time to relapse, worse baseline prognostic criteria, and worse clinical outcome to targeted therapy. Additional insight into the biology of sRCC is needed to develop alternative therapeutics.
    Clinical Genitourinary Cancer 09/2014; 13(2). DOI:10.1016/j.clgc.2014.08.011 · 1.69 Impact Factor
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    ABSTRACT: Introduction Abiraterone (AA) is a CYP17 inhibitor that prolongs survival in men with metastatic castration-resistant prostate cancer (mCRPC). Data suggest similar pharmacokinetics of 250–500 mg of AA with high-fat meals (‘low-dose’) and 1000 mg in the fasting state (‘full-dose’). Ketoconazole (KT) is a less potent CYP17 inhibitor previously widely used in mCRPC. Objective To study outcomes of men with mCRPC treated with low-dose AA and/or with prior exposure to KT. Patients and methods Retrospective chart review of all men treated with AA at the Princess Margaret Cancer Centre between November 2009 and March 2013. Outcome measures were prostate-specific antigen response rate (PSA-RR), biochemical progression-free survival (bPFS), treatment duration and overall survival (OS). Associations between AA dose or prior KT and outcomes were assessed using chi-square test for PSA-RR and log-rank test for bPFS, treatment duration and OS. Results In total, 111 men who received AA were evaluable, of which 21 received low-dose AA and 23 received prior KT. There was a non-significant difference in PSA-RR (43% versus 32%, p = 0.37), but no significant differences in median bPFS, median treatment duration and median OS (18.7 versus 16.6 months, p = 0.25) in the full and low-dose cohorts respectively, and for those who received prior KT or not (PSA-RR 48% versus 38%, p = 0.4; median OS 24.2 versus 16.5 months, p = 0.066, respectively). Conclusions Low-dose AA or prior KT treatment were not associated with poorer outcome in men with mCRPC treated with AA. These observations may have implications for drug sequencing and dose in resource-limited settings.
    European Journal of Cancer 09/2014; 50(14). DOI:10.1016/j.ejca.2014.06.004 · 4.82 Impact Factor
  • 39th ESMO Congress (ESMO); 09/2014
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    ABSTRACT: Purpose A multicenter, randomized phase II trial, RECORD-3, was conducted to compare first-line everolimus followed by sunitinib at progression with the standard sequence of first-line sunitinib followed by everolimus in patients with metastatic renal cell carcinoma. Patients and Methods RECORD-3 used a crossover treatment design. The primary objective was to assess progression-free survival (PFS) noninferiority of first-line everolimus compared with first-line sunitinib. Secondary end points included combined PFS for each sequence, overall survival (OS), and safety. Results Of 471 enrolled patients, 238 were randomly assigned to first-line everolimus followed by sunitinib, and 233 were randomly assigned to first-line sunitinib followed by everolimus. The primary end point was not met; the median PFS was 7.9 months for first-line everolimus and 10.7 months for first-line sunitinib (hazard ratio [HR], 1.4; 95% CI, 1.2 to 1.8). Among patients who discontinued first-line, 108 (45%) crossed over from everolimus to second-line sunitinib, and 99 (43%) crossed over from sunitinib to second-line everolimus. The median combined PFS was 21.1 months for sequential everolimus then sunitinib and was 25.8 months for sequential sunitinib then everolimus (HR, 1.3; 95% CI, 0.9 to 1.7). The median OS was 22.4 months for sequential everolimus and then sunitinib and 32.0 months for sequential sunitinib and then everolimus (HR, 1.2; 95% CI, 0.9 to 1.6). Common treatment-emergent adverse events during first-line everolimus or sunitinib were stomatitis (53% and 57%, respectively), fatigue (45% and 51%, respectively), and diarrhea (38% and 57%, respectively). Conclusion Everolimus did not demonstrate noninferiority compared with sunitinib as a first-line therapy. The trial results support the standard treatment paradigm of first-line sunitinib followed by everolimus at progression. (C) 2014 by American Society of Clinical Oncology
    Journal of Clinical Oncology 07/2014; 32(25). DOI:10.1200/JCO.2013.54.6911 · 17.88 Impact Factor
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    ABSTRACT: Carbohydrate associated antigen (CA19-9) has been approved by the FDA as a biomarker for monitoring treatment effect in pancreatic cancer. However, the value of serum CA19-9 as a biomarker of response to chemotherapy in bile duct cancer is unclear. The aim of this study was to determine if a decline in CA19-9 (CA19-9 response) during chemotherapy is predictive of survival in patients with inoperable bile duct cancer. Consecutive patients with inoperable bile duct cancer treated at a University Hospital were retrospectively included in an investigational cohort (n=212). Three validation cohorts were established including patients 1) participating in phase I/II trials at a Danish Hospital (n=71), 2) identified retrospectively in a Canadian cohort (n=196) and 3) randomized in the ABC-02 trial (n=410). Patients with a baseline CA19-9 and at least one CA19-9 value measured 10-12 weeks after the start of chemotherapy were included. Multivariate Cox regression analyses were performed. Patients meeting the criteria to be included were 54 in the investigational cohort and 34, 68 and 148 in the three validation sets, respectively. Multivariate analysis included radiological response, performance status, bilirubin, gender, site of cancer, extend of disease, CA19-9 at baseline and age. A hazard ratio (HR) of 0.60 (95%CI: 0.44-0.80, p=0.0005) for death in CA19-9 responders was reached in the investigational cohort. The predictive value of CA 19-9 response was confirmed in all three validation cohorts. CA19-9 response is a robust predictor of survival in patients with inoperable bile duct cancer in four independent data sets. Copyright © 2015. Published by Elsevier Ltd.
    Annals of Oncology 06/2014; 25(suppl 2):ii13-ii13. DOI:10.1093/annonc/mdu164.22 · 6.58 Impact Factor
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    ABSTRACT: The benefit of cytoreductive nephrectomy (CN) for overall survival (OS) is unclear in patients with synchronous metastatic renal cell carcinoma (mRCC) in the era of targeted therapy.
    European Urology 06/2014; 66(4). DOI:10.1016/j.eururo.2014.05.034 · 12.48 Impact Factor

Publication Stats

3k Citations
803.59 Total Impact Points

Institutions

  • 2005–2015
    • The Princess Margaret Hospital
      Toronto, Ontario, Canada
  • 2004–2015
    • University of Toronto
      • Department of Radiation Oncology
      Toronto, Ontario, Canada
  • 2005–2014
    • University Health Network
      • Department of Medical Oncology
      Toronto, Ontario, Canada
  • 2009
    • Cancer Centre London - Parkside
      Londinium, England, United Kingdom
    • Harvard University
      Cambridge, Massachusetts, United States