Faculty Bibliography

Several studies demonstrate that use of commonly prescribed medications is associated with improved survival in various malignancies. Methods of classifying medication use in many of these studies, however, do not account for intermittent or cumulative use. Moreover, there are limited data in kidney cancer. Therefore, we performed a population-based cohort study utilizing healthcare databases in Ontario, Canada. We identified patients aged ≥65 with an incident diagnosis of kidney cancer between 1997 and 2013 and examined use of nine putative anti-neoplastic medications using prescription claims. Cox proportional hazard models evaluated the association of medication exposure on cancer-specific and overall survival. We conducted three separate analyses: the effect of cumulative duration of exposure to the study medications on outcomes, the effect of current exposure (in a binary nature) and the effect of exposure at diagnosis. During the 16-year study period, we studied 9,124 patients. Increasing cumulative use of angiotensin-converting enzyme inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs) and selective serotonin reuptake inhibitors were associated with markedly improved cancer-specific survival; increasing use of NSAIDs was associated with markedly improved overall survival. These results were generally discordant with analyses evaluating the effect of current use and exposure at diagnosis. In conclusion, pharmacoepidemiology studies may be sensitive to the method of analysis; cumulative use analyses may be the most robust as it accounts for intermittent use and supports a dose-outcome relationship. Prospective studies are needed to confirm whether patients diagnosed with kidney cancer should be started on an angiotensin-converting enzyme inhibitor, NSAID or selective serotonin reuptake inhibitor to improve survival.

BACKGROUND:Postchemotherapy retroperitoneal lymph node dissection (pcRPLND) is indicated in testicular cancer patients with normalised or plateaued serum tumour markers and residual retroperitoneal lesions >1cm. Challenges remain in predicting postchemotherapy residual mass (pcRM) histology, which may lead to unnecessary surgery. OBJECTIVE:To develop an accurate model to predict pcRM histology in patients with nonseminomatous germ cell tumours (NSGCTs). DESIGN, SETTING, AND PARTICIPANTS:A retrospective review of 335 patients undergoing pcRPLND for metastatic NSGCTs to develop a model to predict benign histology in retroperitoneal pcRM. Our model was compared with others and externally validated. INTERVENTION:Chemotherapy and pcRPLND. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:Multivariable logistic regression to evaluate the presence of benign histology, and fractional polynomials to allow for a nonlinear association between continuous variables and the outcome. The final Princess Margaret model (PMM) was selected based on the number of variables used, reliability, and discriminative capacity to predict benign pcRM. RESULTS AND LIMITATIONS:PMM included the presence of teratoma in the orchiectomy, prechemotherapy α-fetoprotein, prechemotherapy mass size, and change in mass size during chemotherapy. Model specificity was 99.3%. Compared with Vergouwe et al's model, PMM had significantly better accuracy (C statistic 0.843 vs 0.783). PMM appropriately identified a larger number of patients for whom pcRPLND can safely be avoided (13.9% vs 0%). Validated in external cohorts, the model retained high discrimination (C statistic 0.88 and 0.80). Larger and prospective studies are needed to further validate this model. CONCLUSIONS:Our clinical model, externally validated, showed improved discriminative ability in predicting pcRM histology when compared with other models. The higher accuracy and reduced number of variables make this a novel and appealing model to use for patient counselling and treatment strategies. PATIENT SUMMARY:Princess Margaret model accurately predicted postchemotherapy benign histology. These results might have clinical impact by avoiding unnecessary retroperitoneal lymph node dissection and consequently changing the paradigm of advanced testicular cancer treatment.

INTRODUCTION/BACKGROUND:Non-muscle-invasive bladder cancer (NMIBC) accounts for 75-85% of all urothelial bladder cancers (UBC). Many UBC patients are also afflicted by diabetes mellitus (DM). It has been postulated that several oral hypoglycemic agents could impact disease-specific survival (DSS), but the data are sparse among NMIBC patients. Our primary objective was to evaluate the impact of metformin on DSS and overall survival (OS) in NMIBC patients. METHODS:This is a retrospective, population-based study that used linked administrative databases to identify diabetic patients ≥66 years who were subsequently diagnosed with NMIBC in Ontario between 1992 and 2012. Cumulative use of metformin and other hypoglycemic agent were calculated before and after NMIBC diagnosis. DSS and OS were estimated using multivariable competing risk and Cox proportional hazards models, respectively. RESULTS:A total of 1742 subjects were included in the study. After a median followup of 5.2 years, 1122 (64%) had died, including 247 (15%) deaths as a result of UBC. On multivariable analysis, cumulative duration of metformin use after NMIBC diagnosis did not appear to impact DSS (hazard ratio [HR] 1.1; 95% confidence interval [CI] 0.92-1.2), whereas glyburide use appeared to have a detrimental effect (HR 1.17; 95% CI 1.02-1.3). None of the other hypoglycemic agents had an impact on OS. CONCLUSIONS:In this large, population-based study, we have provided further evidence that metformin use does not significantly impact DSS among diabetic patients diagnosed with NMIBC. However, our findings demonstrate that glyburide use inversely affects DSS. The detrimental effect of glyburide on DSS will require further validation.

Testicular cancer is the most common malignancy in young men, and the incidence is increasing in most countries worldwide. The vast majority of patients present with clinical stage I disease, and surveillance is being increasingly adopted as the preferred management strategy. At the time of diagnosis, patients on surveillance are often counselled about their risk of relapse based on risk factors present at diagnosis, but this risk estimate becomes less informative in patients that have survived a period of time without experiencing relapse. Conditional survival estimates, on the other hand, provide information on a patient's evolving risk of relapse over time. In this review, we describe the concept of conditional survival and its applications for surveillance of clinical stage I seminoma and nonseminoma germ cell tumours. These estimates can be used to tailor surveillance protocols based on future risk of relapse within risk subgroups of seminoma and nonseminoma, which may reduce the burden of follow-up for some patients, physicians, and the health care system. Furthermore, conditional survival estimates provide patients with a meaningful, evolving risk estimate and may be helpful to reassure patients and reduce potential anxiety of being on surveillance.

PURPOSE:After chemotherapy, approximately 50% of patients with metastatic testicular germ cell tumors (GCTs) who undergo retroperitoneal lymph node dissections (RPNLDs) for residual masses have fibrosis. Radiomics uses image processing techniques to extract quantitative textures/features from regions of interest (ROIs) to train a classifier that predicts outcomes. We hypothesized that radiomics would identify patients with a high likelihood of fibrosis who may avoid RPLND. PATIENTS AND METHODS:Patients with GCT who had an RPLND for nodal masses > 1 cm after first-line platinum chemotherapy were included. Preoperative contrast-enhanced axial computed tomography images of retroperitoneal ROIs were manually contoured. Radiomics features (n = 153) were used to train a radial basis function support vector machine classifier to discriminate between viable GCT/mature teratoma versus fibrosis. A nested 10-fold cross-validation protocol was used to determine classifier accuracy. Clinical variables/restricted size criteria were used to optimize the classifier. RESULTS:Seventy-seven patients with 102 ROIs were analyzed (GCT, 21; teratoma, 41; fibrosis, 40). The discriminative accuracy of radiomics to identify GCT/teratoma versus fibrosis was 72 ± 2.2% (area under the curve [AUC], 0.74 ± 0.028); sensitivity was 56.2 ± 15.0%, and specificity was 81.9 ± 9.0% ( P = .001). No major predictive differences were identified when data were restricted by varying maximal axial diameters (AUC range, 0.58 ± 0.05 to 0.74 ± 0.03). The prediction algorithm using clinical variables alone identified an AUC of 0.76. When these variables were added to the radiomics signature, the best performing classifier was identified when axial masses were limited to diameter < 2 cm (accuracy, 88.2 ± 4.4; AUC, 0.80 ± 0.05; P = .02). CONCLUSION:A predictive radiomics algorithm had a discriminative accuracy of 72% that improved to 88% when combined with clinical predictors. Additional independent validation is required to assess whether radiomics allows patients with a high predicted likelihood of fibrosis to avoid RPLND.

BACKGROUND:Some centers offer assisted reproductive technologies (ARTs) [intra-uterine insemination (IUI) and in-vitro fertilization (IVF)], to treat certain couples with male factor infertility without having the men assessed by male infertility specialists. We sought to compare characteristics of couples having or not having prior ART use. METHODS:We used our prospectively collected database to identify men undergoing an initial evaluation for male infertility between 1995-2017. We obtained data on patient demographics, use of IUI and IVF, and semen analysis parameters. We used multivariable logistic regression to identify characteristics associated with prior use of ART. RESULTS:One thousand and five hundred forty-five out of 8,962 (17.2%) men reported use of ARTs prior to evaluation. Of these, 258 tried both IUI and IVF. More than one attempt was reported in 470 (37.2%) and 154 (28.2%) of men with prior IUI and IVF, respectively. Younger male age [adjusted odds ratio (aOR) 0.97/year; 95% confidence interval (CI), 0.95 to 0.99], older female partner age (aOR 1.07/year; 95% CI, 1.04 to 1.10), and year of visit (aOR 1.05/year; 95% CI, 1.01 to 1.09) were significantly associated with prior IUI. Older female partner age (aOR 1.07/year; 95% CI, 1.02 to 1.12) was significantly associated with prior IVF, but not male age or year of visit. Semen analysis parameters were not associated with prior ART. CONCLUSIONS:The prior use of ART is common among men presenting for an initial evaluation at a male infertility specialty clinic. Older female partner age was associated with use of reproductive technologies prior to evaluation, however, semen analysis parameters were not.

BACKGROUND:Patients on surveillance for clinical stage I (CSI) testicular cancer are counseled regarding their baseline risk of relapse. The conditional risk of relapse (cRR), which provides prognostic information on patients who have survived for a period of time without relapse, have not been determined for CSI testicular cancer. OBJECTIVE:To determine cRR in CSI testicular cancer. DESIGN, SETTING, AND PARTICIPANTS:We reviewed 1239 patients with CSI testicular cancer managed with surveillance at a tertiary academic centre between 1980 and 2014. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: cRR estimates were calculated using the Kaplan-Meier method. We stratified patients according to validated risk factors for relapse. We used linear regression to determine cRR trends over time. RESULTS AND LIMITATIONS:At orchiectomy, the risk of relapse within 5 yr was 42.4%, 17.3%, 20.3%, and 12.2% among patients with high-risk nonseminomatous germ cell tumor (NSGCT), low-risk NSGCT, seminoma with tumor size ≥3cm, and seminoma with tumor size <3cm, respectively. However, for patients without relapse within the first 2 yr of follow-up, the corresponding risk of relapse within the next 5 yr in the groups was 0.0%, 1.0% (95% confidence interval [CI] 0.3-1.7%), 5.6% (95% CI 3.1-8.2%), and 3.9% (95% CI 1.4-6.4%). Over time, cRR decreased (p≤0.021) in all models. Limitations include changes to surveillance protocols over time and few late relapses. CONCLUSIONS:After 2 yr, the risk of relapse on surveillance for CSI testicular cancer is very low. Consideration should be given to adapting surveillance protocols to individualized risk of relapse based on cRR as opposed to static protocols based on baseline factors. This strategy could reduce the intensity of follow-up for the majority of patients. PATIENT SUMMARY:Our study is the first to provide data on the future risk of relapse during surveillance for clinical stage I testicular cancer, given a patient has been without relapse for a specified period of time.

There is conflicting evidence whether diabetes is associated with survival outcomes in patients undergoing a nephrectomy for renal cell carcinoma. We performed a retrospective review of 1034 patients undergoing nephrectomy for unilateral, M0, renal cell carcinoma between 2000 and 2016 at a tertiary academic center. Inverse probability of treatment weights were derived from a propensity score model based on various clinical, surgical, and pathological characteristics. We used Cox proportional hazard models to evaluate the association between diabetes and disease-free survival, cancer-specific survival, and overall survival in the sample weighted by the inverse probability of treatment weights. Furthermore, to evaluate whether severity of diabetes was associated with survival outcomes, we performed separate analyses where inverse probability of treatment weights were computed based on the probability of having diabetes that was controlled by medication. Of the 1034 patients, 180 (17 %) had diabetes. Of these, 139 (77 %) patients required medications for diabetes control while the remaining 41 (23 %) had diet controlled diabetes. Median follow-up was 50 months (IQR 17-86). Diabetes at the time of surgery was not significantly associated with disease-free survival (HR 1.11, 95 % CI 0.64 -1.91), cancer-specific survival (HR 0.96, 95 % CI 0.49-1.91), or overall survival (HR 1.28, 95 % CI 0.84-1.95). We found similar results when we compared diabetics controlled with medication vs. non-diabetics or diet controlled diabetics. In summary, we found no significant association between diabetes and survival outcomes in patients undergoing nephrectomy for M0 renal cell carcinoma. These results suggest that diabetics should be treated and followed in a similar manner to non-diabetics.