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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.  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
3.  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
4.  External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study 
The Lancet. Oncology  2013;14(2):141-148.
The International Metastatic Renal-Cell Carcinoma Database Consortium model offers prognostic information for patients with metastatic renal-cell carcinoma. We tested the accuracy of the model in an external population and compared it with other prognostic models.
We included patients with metastatic renal-cell carcinoma who were treated with first-line VEGF-targeted treatment at 13 international cancer centres and who were registered in the Consortium’s database but had not contributed to the initial development of the Consortium Database model. The primary endpoint was overall survival. We compared the Database Consortium model with the Cleveland Clinic Foundation (CCF) model, the International Kidney Cancer Working Group (IKCWG) model, the French model, and the Memorial Sloan-Kettering Cancer Center (MSKCC) model by concordance indices and other measures of model fit.
Overall, 1028 patients were included in this study, of whom 849 had complete data to assess the Database Consortium model. Median overall survival was 18·8 months (95% 17·6–21·4). The predefined Database Consortium risk factors (anaemia, thrombocytosis, neutrophilia, hypercalcaemia, Karnofsky performance status <80%, and <1 year from diagnosis to treatment) were independent predictors of poor overall survival in the external validation set (hazard ratios ranged between 1·27 and 2·08, concordance index 0·71, 95% CI 0·68–0·73). When patients were segregated into three risk categories, median overall survival was 43·2 months (95% CI 31·4–50·1) in the favourable risk group (no risk factors; 157 patients), 22·5 months (18·7–25·1) in the intermediate risk group (one to two risk factors; 440 patients), and 7·8 months (6·5–9·7) in the poor risk group (three or more risk factors; 252 patients; p<0·0001; concordance index 0·664, 95% CI 0·639–0·689). 672 patients had complete data to test all five models. The concordance index of the CCF model was 0·662 (95% CI 0·636–0·687), of the French model 0·640 (0·614–0·665), of the IKCWG model 0·668 (0·645–0·692), and of the MSKCC model 0·657 (0·632–0·682). The reported versus predicted number of deaths at 2 years was most similar in the Database Consortium model compared with the other models.
The Database Consortium model is now externally validated and can be applied to stratify patients by risk in clinical trials and to counsel patients about prognosis.
PMCID: PMC4144042  PMID: 23312463
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.  Impact of bone and liver metastases on patients with renal cell carcinoma treated with targeted therapy 
European urology  2013;65(3):577-584.
The skeleton and liver are frequently involved sites of metastasis in patients with metastatic renal cell carcinoma (RCC).
The purpose of this study was to analyze outcomes based on the presence of bone metastases (BM) and/or liver metastases (LM) in patients with RCC treated with targeted therapy.
Design, Setting and Participants
We conducted a review from the International Metastatic RCC Database Consortium (IMDC) of 2,027 patients with metastatic RCC.
Outcome Measurements and Statistical Analysis
We analyzed the impact of site of metastasis on overall survival (OS) and time-to-treatment failure (TTF). Statistical analyses were performed using multivariable Cox regression.
Results and Limitations
Presence of BM was 34% overall and when stratified by IMDC risk groups was 27%, 33%, and 43% in favorable, intermediate, and poor-risk groups, respectively (pitalic>0.001). Presence of LM was 19% overall and higher in the poor-risk patients (23%) compared to the favorable or intermediate-risk groups (17%) (p=0.003). When patients were classified into four groups based on the presence of BM and/or LM the hazard ratio (HR), adjusted for IMDC risk factors, was 1.4 (95% Confidence Interval (CI) 1.22–1.62) for BM, 1.42 (95% CI 1.17–1.73) for LM, and 1.82 (95% CI 1.47–2.26) for both BM and LM compared to other metastatic sites (pbold>0.0001). The prediction model performance for OS was significantly improved when BM and LM were added to the IMDC prognostic model (likelihood ratio test p<0.0001). Data in this analysis was collected retrospectively.
The presence of BM and LM in patients treated with targeted agents has a negative impact on survival. Patients with BM and/or LM may benefit from earlier inclusion on clinical trials of novel agents or combination-based therapies.
PMCID: PMC4123121  PMID: 23962746
Bone metastases; Liver metastases; mTOR inhibitors; Outcome; Renal cell carcinoma; VEGF therapy
7.  Progression-Free Survival as a Predictor of Overall Survival in Metastatic Renal Cell Carcinoma Treated With Contemporary Targeted Therapy 
Cancer  2010;117(12):10.1002/cncr.25750.
The majority of metastatic renal cell carcinoma (mRCC) clinical trials that examined targeted agents used progression-free survival (PFS) as the primary endpoint. Whether PFS can be used as a predictor of overall survival (OS) is unknown.
Patients from 12 cancer centers who received targeted therapy for mRCC were identified. Landmark analyses for progression at 3 months and 6 months after drug initiation were performed to minimize lead-time bias. A proportional hazards model was used to assess the utility of PFS for predicting OS.
In total, 1158 patients were included. The median follow-up was 30.6 months, the median age was 60 years, and the median Karnofsky performance status was 80%. For the entire cohort, the median PFS was 7.6 months, and the median OS was 19.7 months. In the landmark analysis, the median OS for patients who progressed at 3 months was 7.8 months compared with 23.6 months for patients who did not progress (log-rank test; P < .0001). Similarly, for patients who progressed at 6 months, the median OS was 8.6 months compared with 26 months for patients who did not progress (P < .0001). Compared with those who did not progress, for the patients who progressed at 3 months and at 6 months, the hazard ratios for death adjusted for adverse prognostic factors were 3.05 (95% confidence interval, 2.42-3.84) and 2.96 (95% confidence interval, 2.39-3.67), respectively. Similar results were demonstrated with landmark analyses at 9 months and at 12 months and in the bootstrap validation. Kendall tau rank correlation and a Fleischer model demonstrated a statistically significant dependent correlation.
PFS at 3 months and at 6 months predicted OS, and the current results indicated that PFS may be a meaningful intermediate endpoint for OS in patients with mRCC who receive treatment with novel agents.
PMCID: PMC3856357  PMID: 21656741
progression-free survival; overall survival; surrogate endpoints; vascular endothelial growth factor; metastatic renal cell carcinoma
8.  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
10.  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
11.  Canadian guideline on genetic screening for hereditary renal cell cancers 
Hereditary renal cell cancer (RCC) is an ideal model for germline genetic testing. We propose a guideline of hereditary RCC specific criteria to suggest referral for genetic assessment.
A review of the literature and stakeholder resources for existing guidelines or consensus statements was performed. Referral criteria were developed by expert consensus.
The criteria included characteristics for patients with RCC (age ≤45 years, bilateral or multifocal tumours, associated medical conditions and non-clear cell histologies with unusual features) and for patients with or without RCC, but a family history of specific clinical or genetic diagnoses.
This guideline represents a practical RCC-specific reference to allow healthcare providers to identify patients who may have a hereditary RCC syndrome, without extensive knowledge of each syndrome. RCC survivors and their families can also use the document to guide their discussions with healthcare providers about their need for referral. The criteria refer to the most common hereditary renal tumour syndromes and do not represent a comprehensive or exclusive list. Prospective validation of the criteria is warranted.
PMCID: PMC3854468  PMID: 24319509
15.  A case of metastatic adenocarcinoma of the prostate arising in a meningioma 
We present the case of a 70-year-old man who had a prostate adenocarcinoma that metastatized to a previously unknown cranial meningioma. Central nervous system (CNS) metastases are very uncommon in patients with prostate cancer, and metastases to pre-existing primary CNS tumours are even more uncommon. Rare events like this can cause diagnostic uncertainty, as shown by this case. This case is a reminder for clinicians to consider prostate metastases in patients with known prostate carcinoma and focal neurological symptoms.
PMCID: PMC2692142  PMID: 19543455
16.  Application of the International Germ Cell Consensus Classification to the Nova Scotia population of patients with germ cell tumours 
The International Germ Cell Consensus Classification (IGCCC) is the internationally accepted, clinically based prognostic classification used to assist in the management and research of metastatic germ cell tumours (GCTs). The goal of this study was to determine whether the IGCCC is applicable to a population-based cohort.
We completed a retrospective chart review of patients who received diagnoses of GCT in Nova Scotia between 1984 and 2004 and who received treatment with platin-based chemotherapy for metastatic disease. We assigned the IGCCC to each patient based on the site of the primary lesion, the presence or absence of nonpulmonary visceral metastases and prechemotherapy tumour marker values. We calculated Kaplan–Meier estimates of 5-year progression-free survival (PFS) and overall survival for each IGCCC group.
The study cohort comprised 129 patients. The distribution and outcomes in each group of patients in Nova Scotia was similar to that published in the IGCCC. Among patients with nonseminoma GCTs (NSGCT) 61% had good, 22% had intermediate and 17% had poor prognoses. Among those with seminomas, 85% had good and 15% had intermediate prognoses. Among patients with NSGCTs, the 5-year PFS was 90%, 69% and 55%, and the 5-year overall survival was 94%, 84%, 61% in the good, intermediate, and poor prognostic categories respectively. Among patients with seminomas, the 5-year PFS was 95% and 50% and the 5-year overall survival was 94% and 50% in the good and intermediate prognostic categories, respectively.
The IGCCC seems applicable to a population-based cohort, with similar distribution of categories and clear prognostic ability.
PMCID: PMC2666903  PMID: 19424465
17.  Hereditary renal cell carcinoma associated with von Hippel–Lindau disease: a description of a Nova Scotia cohort 
von Hippel–Lindau (VHL) disease is an autosomal dominant condition characterized by the development of benign and malignant tumours, including cases of renal cell carcinoma (RCC). Early detection of RCC through routine surveillance can lead to decreased morbidity and mortality. Data on the number of patients in Nova Scotia (NS) who have VHL disease, disease manifestations and the frequency and mode of the surveillance have not previously been collected or reported. This project was designed to obtain that information.
The number and management of patients with VHL disease was determined by multiple sources: the Maritime Medical Genetics Service, patient charts, and pathology, radiology and laboratory data. The actual surveillance being performed was compared with that recommended in the literature.
Twenty-one patients from 11 families in NS were identified. Manifestations included cases of RCC (31.6%), central nervous system (CNS) hemangioblastoma (73.7%), retinal hemangioma (47.4%), renal cyst (47.4%) and pheochromocytoma (10.5%). Of the 6 patients with RCC, 4 had bilateral tumours, 2 required kidney transplants and 1 developed metastatic disease. Routine surveillance was being done for the CNS in 62.5% of patients, retina in 47.4%, abdomen in 43.8% and urine catecholamines in only 10.5%. Only 1 of the 6 patients who developed RCC was undergoing routine abdominal imaging. Surveillance investigations were ordered by a number of different specialists.
Patients with VHL disease in NS have a number of manifestations associated with their disease, including RCC, in a similar frequency to that reported in the literature. The surveillance of these patients is suboptimal in frequency and coordination. von Hippel–Lindau disease is a complex condition that requires a coordinated approach to care to ensure proper surveillance and treatment. Our study highlights current deficiencies and offers an enormous opportunity for improvement.
PMCID: PMC2645893  PMID: 19293973
18.  Summary of the first annual Genitourinary Medical Oncology Conference Renal Cell Carcinoma Forum 
Canadian Urological Association Journal  2007;1(2 Suppl):S6-S12.
The first annual Canadian Genitourinary Medical Oncology Conference was held in June 2006 before the Canadian Urology Association Annual Meeting. This article summarizes 3 presentations that took place as part of the Renal Cell Carcinoma Forum: “Treatment of Metastatic Renal Cell Carcinoma: 2006 and Beyond” was presented by Dr. Bernard Escudier; “Practical Experience with Targeted Therapy,” by Dr. Lori Wood; and “Sarcomatoid Renal Cell Carcinoma,” by Dr. Neil Reaume.
PMCID: PMC2422956  PMID: 18542786
21.  Skeletal cryptococcosis: Case report and review of the literature 
A case of isolated cryptococcal skull infection is presented in a patient with unexplained CD4 lymphopenia and chronic hepatitis B. All cases of this disease reported in the English literature from 1956 to the present are reviewed. The literature suggests that skeletal cryptococcosis is manifested in only 5% to 10% of recognized cases of disseminated cryptococcosis and that isolated skeletal disease without evidence of other tissue involvement is even less common. When isolated bony disease does occur it tends to occur in immunocompromised hosts, particularly those with defects of cell mediated immunity. Any bony site can be involved, most commonly the vertebrae, with the presentation often being a soft tissue swelling and pain in the affected area. Systemic constitutional symptoms occur in a minority of patients. Radiographic investigations are nonspecific and the gold standard of diagnosis remains culture isolation from bone tissue. The most commonly employed therapy for isolated bone disease is amphotericin alone or combined with surgical debridement. The new azoles may have a role in future therapy.
PMCID: PMC3327391  PMID: 22514429
Bone infection; Cryptococcus; Fluconazole; Osteomyelitis; Skeletal infection

Results 1-21 (21)