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1.  Efficacy of Targeted Therapy for Metastatic Renal Cell Carcinoma in the Elderly Patient Population 
Clinical genitourinary cancer  2014;12(5):354-358.
Targeted therapy has become the mainstay of treatment for metastatic renal cell carcinoma (mRCC), and the efficacy of this therapy in the older population is poorly understood. Data from 1381 patients with mRCC treated with first-line anti-vascular endothelial growth factor (VEGF) therapy were collected through the International mRCC Database Consortium from 12 centers. When adjusted for poor prognostic factors, age 75 years and older was not found to be associated with poorer overall survival or shorter treatment duration. This suggests that advanced age alone should not preclude a patient from targeted therapy.
Targeted therapy has become the mainstay of treatment for 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.
All patients (n = 1381) were treated with front-line targeted therapy; 144 (10%) were 75 years old or older. Six patients (4%) were favorable risk, 99 patients (69%) intermediate risk, and 39 patients (27%) poor risk according to Heng Journal of Clinical Oncology 2009 prognostic factors. The initial treatment for those ≥ 75 years of age was sunitinib (n = 98), sorafenib (n = 35), bevacizumab (n = 7), and AZD217 (n = 4). Twenty-three percent of older patients and 39% of the younger patients went on to receive second-line therapy (P < .0001). The overall response rate, median treatment duration, and overall survival for the older versus younger group were 18% versus 25% (P = .0975), 5.5 months versus 7.5 months (P = .1388), and 16.8 months versus 19.7 months (P = .3321), respectively. When adjusted for poor prognostic factors, age 75 years and older was not found to be associated with poorer overall survival (hazard ratio [HR], 1.002; 95% confidence interval [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.
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.
PMCID: PMC4156559  PMID: 24819320
Age; Geriatric; mRCC; Prognostic factors; Vascular endothelial growth factor
2.  A multicentre analysis of abiraterone acetate in Canadian patients with metastatic castration-resistant prostate cancer 
Canadian Urological Association Journal  2014;8(9-10):E583-E590.
The COU-AA-301 trial showed that abiraterone acetate (abiraterone), an oral cytochrome p450 CYP17 inhibitor, improved survival for men with metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel. To better understand the non-clinical trial experience with abiraterone, we undertook a multicentre retrospective analysis of Canadian mCRPC patients treated with abiraterone.
Consecutive patients with mCRPC who received abiraterone post-docetaxel were identified using centralized pharmacy records. These patients came from 5 Canadian tertiary cancer centres. Patients who received abiraterone for approved indications were included. Demographics, prognostic factors, treatment outcomes and adverse events were abstracted.
We included 187 patients who initiated abiraterone between January 2011 and June 2012. The median age at diagnosis and abiraterone start was 65 and 73 years, respectively. Seventy-three (39%) patients had metastatic disease at diagnosis. The Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, 2 and 3 was noted in 17, 96, 39 and 8 patients, respectively. The median prostate-specific antigen (PSA) at abiraterone start was 132, with a median PSA doubling time of 2.8 months. The median follow-up of patients still on active follow-up was 13 months. The proportion of patients achieving a ≥50% PSA reduction was 64/177 (36%). PSA progression-free survival was 3.5 months (95% confidence interval [CI], 3.0, 4.0). Median overall survival from start of abiraterone was 11 months (95% CI, 8.0, 13) and 38 months (95% CI, 31, 41) from date of mCRPC. Anemia and fatigue were the most commonly reported adverse events.
This study carries the inherent limitations of a retrospective chart review. The outcomes in this series of men treated with abiraterone in a non-trial setting were expected, considering previous clinical trials. Our results, therefore, support the generalizability of the COU-AA-301 study results.
PMCID: PMC4164543  PMID: 25295126
3.  Treatment of muscle-invasive bladder cancer in Canada: A survey of genitourinary medical oncologists and urologists 
Uptake of neoadjuvant chemotherapy (NC) for muscle invasive bladder cancer (MIBC) has been low despite evidence of a survival benefit. The primary aim of this study was to better understand why the rates are low and determine what factors specifically influence the decision to recommend NC for MIBC.
A 31-question survey was emailed between 2009 and 2011 to medical oncologists belonging to the Canadian Association of Genitourinary Medical Oncologists (CAGMO); and to urologists belonging to the Canadian Urologic Oncology Group (CUOG). We gathered data on practice characteristics, referrals for NC, factors influencing NC use, and chemotherapy regimens offered. Responses were summarized using descriptive statistics.
In total, 26/30 (87%) medical oncologists and 25/84 (30%) urologists, who were primarily academic, completed the survey. Most clinicians (medical oncologists 96%, urologists 88%) recommended NC for MIBC, because they considered it to be the standard of care, but most medical oncologists saw ≤6 referrals annually. Performance status, presence of comorbidities and renal function were key considerations in offering NC. NC was not offered if performance status ≥2 (medical oncologists 38%, urologists 44%), age >80 (medical oncologists 46%, urologists 39%), or glomerular filtration rate ≤40 mL/min (medical oncologists 81%, urologists 50%).
Most academic clinicians in Canada believe that cisplatin-based combination NC is the standard of care for MIBC and recommend it for patients with adequate performance status and renal function. Using a multidisciplinary approach to treat this disease may be one strategy to increase referral rates for NC and uptake of NC.
PMCID: PMC4216285  PMID: 25408794
4.  The association of clinical outcome to first-line VEGF-targeted therapy with clinical outcome to second-line VEGF-targeted therapy in metastatic renal cell carcinoma patients 
Targeted oncology  2013;8(3):203-209.
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.
PMCID: PMC4144038  PMID: 23300029
Association of TKIs; First-line and second-line VEGF inhibitors; Renal cell cancer; Tyrosine kinase inhibitors; VEGF-targeted therapy
5.  Metastatic non clear cell renal cell carcinoma (nccRCC) treated with targeted therapy agents: Characterization of survival outcome and application of the International mRCC Database Consortium (IMDC) Criteria 
Cancer  2013;119(16):2999-3006.
This study aims to apply the International mRCC Database Consortium (IMDC) Prognostic Model in metastatic non clear cell renal cell carcinoma (nccRCC). Additionally, the survival outcome of metastatic nccRCC patients was characterized.
Data on 2215 (1963 ccRCC/252 nccRCC) patients 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 of favorable, intermediate, and poor prognosis groups according to the IMDC prognostic criteria
The median OS of the entire cohort was 20.9 months. nccRCC patients were of younger age (p<0.0001), more often presented with low Hb (p=0.014) and elevated neutrophils (p=0.0001), but displayed otherwise similar clinicopathological features compared to ccRCC. OS (12.8 vs. 22.3 months; p<0.0001) and time to treatment failure (TTF) (4.2 vs. 7.8 months; p<0.0001) were worse in nccRCC compared to ccRCC. The hazard ratio for death and TTF when adjusted for the prognostic factors was 1.41 (95%CI 1.19, 1.67, p<0.0001) and 1.54 (95% CI 1.33, 1.79, p<0.0001), respectively. The IMDC prognostic model reliably discriminated three risk groups to predict OS and TTF in nccRCC; the median OS and TTF of favorable, intermediate, and poor prognosis groups were 31.4, 16.1, and 5.1 months (p<0.0001) and 9.6, 4.9, and 2.1 months (p<0.0001), respectively.
Although targeted agents have significantly improved the outcome of patients with nccRCC, for the majority survival is still inferior compared to ccRCC. The IMDC prognostic model reliably predicts OS and TTF in nccRCC and ccRCC patients.
PMCID: PMC3934562  PMID: 23696129
non-clear cell renal cell carcinoma; targeted therapies; overall survival; prognostication; Heng risk criteria; IMDC risk model
6.  Improving the outcome of patients with muscle invasive urothelial carcinoma of the bladder with neoadjuvant gemcitabine/cisplatin chemotherapy: A single institution experience 
Neoadjuvant cisplatin-based chemotherapy prior to radical cystectomy (RC) for muscle invasive urothelial carcinoma of the bladder improves survival. This study was undertaken to determine the rate of neoadjuvant gemcitabine and cisplatin use prior to RC and to assess its effect on the pathologic response rates and cancer-specific survival (CSS) and overall survival (OS).
This retrospective chart review examined all patients having a RC between January 1, 2007 and June 30, 2011. We collected patient demographics, pre-treatment clinical stage, type of chemotherapy, post-RC pathologic data and survival data.
A total of 251 RC were performed of which 160 were for stage cT2–T4 urothelial carcinoma of the bladder. Of the 160 patients, 91 (57%) received neoadjuvant gemcitabine and cisplatin (GC) and 69 (43%) went straight to RC. Patients receiving neoadjuvant GC had a greater chance of achieving a pathologically lower stage compared to the untreated population: pT0 at 21% vs. 3%; non-invasive cancer at 37% vs. 10%; and organ-confined cancer at 60% vs. 33% (p < 0.001). Survival correlated with pathological stage: ≤pT3a patients had a median OS and CSS of 48.8 and 51.2 months compared to an OS and a CSS in ≥pT3b patients of 21.8 and 28.1 months, respectively (p < 0.0001).
Neoadjuvant chemotherapy for urothelial carcinoma of the bladder is more frequently administered at our institution compared to the published literature. We have found that neoadjuvant chemotherapy increases the rate of down-staging, which is associated with a reduced the risk of death from urothelial carcinoma of the bladder.
PMCID: PMC4001664  PMID: 24839503
7.  Conditional survival of patients with metastatic renal-cell carcinoma treated with VEGF-targeted therapy: a population-based study 
The lancet oncology  2012;13(9):10.1016/S1470-2045(12)70285-1.
The advent of targeted therapies in the past 7 years has extended median survival for metastatic renal-cell carcinoma. This improvement in clinical outcome has created a need for new, more accurate prognostic measures. We assessed the use of conditional survival—a measure that accounts for elapsed time since treatment initiation—for prognostication in patients with metastatic renal-cell carcinoma treated with first-line VEGF-targeted therapies.
We obtained data for patients with metastatic renal-cell carcinoma who were treated with a first-line VEGF-targeted therapy between April 7, 2003, and Oct 12, 2010, from our large multi-institutional International mRCC Database Consortium (centres in Canada, the USA, Singapore, Denmark, and South Korea). All histologies, performance statuses, and prognostic risk groups were included. The primary outcome was 2-year conditional survival, defined as the probability of surviving an additional 2 years from a given timepoint since the start of targeted therapy. Secondary analyses included 1-year and 3-year conditional survival, along with stratification of patients by Heng prognostic risk criteria and Karnofsky performance score, and conditional survival based on length of time on therapy. We used the Kaplan-Meier method and a landmark analysis to calculate conditional survival.
In the 1673 patients analysed, median follow-up for alive patients was 20·1 months (IQR 9·0–34·4). We recorded an increase in the 2-year conditional survival probability from 44% (95% CI 41–47) at 0 months to 51% (46–55) at 18 months since beginning targeted therapy. When stratified by the Heng prognostic risk criteria defined at therapy initiation, 2-year conditional survival changed little in the favourable and intermediate groups, but in the poor-risk group, 2-year conditional survival improved from 11% (8–15) at 0 months to 33% (18–48) after 18 months. When conditioned on time on targeted therapy from 0 months to 18 months, 2-year conditional survival improved from 44% (41–47) to 68% (60–75) in the overall population and from 74% (68–79) to 90% (77–96) in the favourable group, 49% (45–53) to 57% (45–67) in the intermediate group, and 11% (8–15) to 73% (43–89) in the poor risk group.
Conditional survival is a clinically useful prediction measure that adjusts prognosis of patients with metastatic renal-cell carcinoma on the basis of survival since treatment initiation or therapy duration. Conditional survival might be especially relevant to adjust prognosis for poor-risk patients.
The Trust Family Fund for Kidney Cancer Research.
PMCID: PMC3856362  PMID: 22877847
8.  Neoadjuvant chemotherapy should be administered to fit patients with newly diagnosed, potentially resectable muscle-invasive urothelial cancer of the bladder (MIBC): A 2013 CAGMO Consensus Statement and Call for a Streamlined Referral Process 
Neoadjuvant chemotherapy (NC) improves overall survival in patients with resectable muscle-invasive urothelial cancer of the bladder (MIBC). However uptake of NC in Canada is dis-appointingly low. Following a detailed literature review and in consultation with urologic oncology, the Canadian Association of Genitourinary Medical Oncologists (CAGMO) has developed a consensus statement for the use of NC in MIBC. Our primary goal is to increase the uptake of NC for MIBC in Canada and improve patient outcomes.
PMCID: PMC3854467  PMID: 24319508
12.  Abiraterone and Increased Survival in Metastatic Prostate Cancer 
The New England journal of medicine  2011;364(21):1995-2005.
Biosynthesis of extragonadal androgen may contribute to the progression of castration-resistant prostate cancer. We evaluated whether abiraterone acetate, an inhibitor of androgen biosynthesis, prolongs overall survival among patients with metastatic castration-resistant prostate cancer who have received chemotherapy.
We randomly assigned, in a 2:1 ratio, 1195 patients who had previously received docetaxel to receive 5 mg of prednisone twice daily with either 1000 mg of abiraterone acetate (797 patients) or placebo (398 patients). The primary end point was overall survival. The secondary end points included time to prostate-specific antigen (PSA) progression (elevation in the PSA level according to prespecified criteria), progression-free survival according to radiologic findings based on prespecified criteria, and the PSA response rate.
After a median follow-up of 12.8 months, overall survival was longer in the abiraterone acetate–prednisone group than in the placebo–prednisone group (14.8 months vs. 10.9 months; hazard ratio, 0.65; 95% confidence interval, 0.54 to 0.77; P<0.001). Data were unblinded at the interim analysis, since these results exceeded the preplanned criteria for study termination. All secondary end points, including time to PSA progression (10.2 vs. 6.6 months; P<0.001), progression-free survival (5.6 months vs. 3.6 months; P<0.001), and PSA response rate (29% vs. 6%, P<0.001), favored the treatment group. Mineralocorticoid-related adverse events, including fluid retention, hypertension, and hypokalemia, were more frequently reported in the abiraterone acetate–prednisone group than in the placebo–prednisone group.
The inhibition of androgen biosynthesis by abiraterone acetate prolonged overall survival among patients with metastatic castration-resistant prostate cancer who previously received chemotherapy. (Funded by Cougar Biotechnology; COU-AA-301 number, NCT00638690.)
PMCID: PMC3471149  PMID: 21612468
13.  Correlates of physical activity in a population-based sample of kidney cancer survivors: an application of the theory of planned behavior 
Over half of kidney cancer survivors (KCS) are completely inactive and only a quarter are meeting physical activity (PA) guidelines. This highlights the need to identify and understand the determinants of PA in this understudied population. The purpose of this study is to determine the social cognitive correlates of PA intention and behavior in KCS using the Theory of Planned Behavior (TPB).
All 1,985 KCS diagnosed between 1996 and 2010 in Alberta, Canada were mailed a self-report survey that consisted of the Godin Leisure Time Exercise Questionnaire and standard TPB items for intention, planning, perceived behavioral control (PBC), affective and instrumental attitudes, and descriptive and injunctive norms. Standard demographic and medical variables were also collected.
Completed surveys were received from 703 of 1,654 (43%) eligible KCS. The TPB was tested using structural equation modelling and demonstrated an adequate-to-good fit to the data [χ² = 256.88, p < .001; TLI = 0.97; CFI = 0.98; RMSEA = 0.06, 90% CI = 0.05-0.06].
There were significant pathways to PA from PBC (ß = 0.18, p = 0.02), planning (ß = 0.22, p < 0.01), and intention (ß = 0.31, p < 0.01); and to planning from intention (ß = 0.81, p < 0.01). In addition, there were significant model pathways to intention from instrumental attitude (ß = 0.28, p = 0.03), descriptive norm (ß = 0.09, p = 0.01), and PBC (ß = 0.52, p < 0.01). Overall, the TPB accounted for 69%, 63%, and 42% of the variance in intention, planning and PA, respectively.
The TPB appears to be a useful model for explaining PA in KCS. All TPB constructs except injunctive norm and affective attitude were useful for explaining intention with PBC emerging as the largest correlate. Developing PA interventions based on the TPB may be effective in promoting PA in KCS and may lead to important improvements in health.
PMCID: PMC3489870  PMID: 22866956
Exercise; Motivation; Social cognitive models; Correlates
15.  A rapid PSA half-life following docetaxel chemotherapy is associated with improved survival in hormone refractory prostate cancer 
Docetaxel chemotherapy prolongs survival in metastatic hormone-refractory prostate cancer (mHRPC), but many patients fail to respond to this therapy and there is potential for serious toxicity. Patients differ in their percent prostate-specific antigen (PSA) decline and rate of PSA decline following treatment. We propose that patients who achieve a rapid rate of PSA decline, measured as a shorter PSA half-life (PSAHL), may experience a longer overall survival (OS) than those who achieve a slower rate of PSA decline.
A chart review of patients treated with docetaxel for mHRPC in Alberta from January 2000 to May 2006 was performed. At 42 days (after 2 cycles) and 84 days (after 4 cycles) following chemotherapy, PSA response and PSAHL were determined. PSAHL could only be determined in patients with a PSA drop from baseline. Optimal PSAHL values for OS stratification were determined using the log-rank chi-square statistic. Survival analysis was carried out using Kaplan-Meier curves and regression analysis.
There were 154 patients who fulfilled the inclusion criteria. Using 42-day postdocetaxel data, no associations with OS could be demonstrated. Using 84-day postdocetaxel data, patients stratified by PSAHL demonstrated a significant difference in OS (15 months vs. 25 months) and this relationship remained following multivariate analysis (hazard ratio 0.08 [0.021–0.34]).
A more rapid rate of PSA decline (PSAHL <70 days) measured after 4 cycles of chemotherapy was associated with a longer OS. This result was independent of other known markers of survival and allowed for a greater survival differentiation than PSA response.
PMCID: PMC2758517  PMID: 19829727
16.  A population-based study examining the effect of tyrosine kinase inhibitors on survival in metastatic renal cell carcinoma in Alberta and the role of nephrectomy prior to treatment 
We performed a retrospective population-based study to assess the impact of tyrosine kinase inhibitors (TKIs) on overall survival (OS) in patients treated for metastatic renal cell carcinoma (mRCC) in Alberta, Canada and to assess the impact of nephrectomy on OS in patients treated with TKIs.
We identified 134 patients who began taking a TKI between December 2003 and June 2007 for mRCC in Alberta. We compared survival in this group to that in an earlier cohort of 141 patients treated with interferon-α (IFN-α) between May 1995 and March 2003. We used the Kaplan–Meier method to determine OS, and we used a Cox proportional hazards model to determine hazard ratios (HRs) and confidence intervals (CIs). We performed multivariate analysis to assess the impact of neprhectomy on OS.
Of the 134 patients treated with TKIs, 81 received treatment in the first-line setting, whereas 53 received treatment after prior IFN-α therapy. All 141 patients from the IFN-α cohort received treatment in the first-line setting. Patients treated with TKIs had an improved OS compared with the IFN-α cohort (HR 0.61, 95% CI 0.45–0.83, p = 0.001). The median OS was 18 months in the TKI group and 10 months in the IFN-α group. The benefit of TKIs was confined to favourable and intermediate risk groups according to the Memorial Sloan-Kettering Cancer Center prognostic model. Prior nephrectomy was associated with improved OS in the TKI cohort, independent of other prognostic factors.
Tyrosine kinase inhibitors improve OS compared with IFN-α in mRCC. In patients treated with TKIs, prior nephrectomy is associated with improved survival independent of other prognostic variables.
PMCID: PMC2723887  PMID: 19672439
18.  Dr. North's rebuttal 
PMCID: PMC2494890  PMID: 18682769
19.  Malignant spinal cord compression secondary to testicular seminoma at the time of initial presentation and at relapse while on surveillance 
We report cases of 2 pure seminoma patients who developed metastatic spinal cord compressions. One patient was diagnosed at age 33 years with stage 1 seminoma and, after undergoing an orchidectomy, chose to be followed on a surveillance protocol. He was lost to follow-up and presented again 22 months later with back pain, leg weakness and sensory loss when his disease recurred as a spinal cord compression. He was treated with urgent surgical decompression and subsequent standard chemotherapy. More than 2 years posttreatment, he is disease-free with normal neurologic function in his lower extremities. The second patient presented at age 44 years with back pain and rapid loss of leg strength and sensation. Investigations revealed a malignant cord compression with lymphatic and vertebral body metastases. On physical examination, the patient was found to have a 6-cm left testicular mass. He was treated with emergency radiotherapy to the region of his cord compression followed by a left inguinal orchidectomy. Pathology confirmed a pure classic seminoma. Postoperatively, he received standard chemotherapy and eventually regained neurologic function in his legs. Although it is rare for malignant spinal cord compression to occur in seminoma patients—either as the initial presentation of disease or as a site of disease recurrence in stage 1 patients on surveillance—it is crucial to consider seminoma as a possible etiology in young men diagnosed with malignant spinal cord compression because timely contemporary treatments for seminoma will cure most of these patients and offer them excellent functional recovery.
PMCID: PMC2422929  PMID: 18542765

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