Real-world Assessment of Clinical Outcomes in Patients with Metastatic Renal Cell Carcinoma with or Without Sarcomatoid Features Treated with First-line Systemic Therapies.

BACKGROUND AND OBJECTIVE: Metastatic renal cell carcinoma (mRCC) patients have been reported to have better outcomes when treated with immunotherapies (IO) compared to targeted therapies (TT). This study aims to evaluate the impact of first-line systemic therapies on survival of mRCC patients with or without sarcomatoid features using real-world data. METHODS: Metastatic RCC patients of International mRCC Database Consortium (IMDC) intermediate or high risk, diagnosed from January 2011 to December 2022, treated with first-line systemic therapies, and with histological documentation of the presence or absence of sarcomatoid features in nephrectomy specimens were identified using the Canadian Kidney Cancer information system. Patients were classified by initial treatment: (1) targeted therapy (TT) used alone or (2) immunotherapy (IO)-based systemic therapies used in combination of either IO-IO or IO-TT. The inverse probability of treatment weighting using propensity scores was used to balance for covariates. Cox proportional hazard models were used to assess the impact of initial treatment received on overall survival (OS). KEY FINDINGS AND LIMITATIONS: Of the 1202 eligible patients, 791 were treated with TT and 411 with IO combinations. Of the patients, 76% were male, and the majority (91%) had a nephrectomy before systemic therapy. In nonsarcomatoid patients (639 TT and 320 IO patients), treatment with IO was associated with improved OS compared with patients treated with TT (median of 72 vs 48 mo, hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.50-0.80, objective response rate [ORR] of 38.5% for IO and 23.5% for TT). In sarcomatoid patients (152 TT and 91 IO patients), treatment with IO was associated with improved OS (median of 48 vs 18 mo, HR 0.41, 95% CI 0.26-0.64, ORR of 49.5% for IO and 13.8% for TT). Similar results were observed in patients with synchronous metastatic disease only. CONCLUSIONS AND CLINICAL IMPLICATIONS: IO treatment was associated with improved survival in mRCC patients. The magnitude of benefit is increased in patients with sarcomatoid mRCC, consequently, identifying the sarcomatoid status early on could help healthcare providers make a better treatment decision. PATIENT SUMMARY: Metastatic renal cell carcinoma (mRCC) patients of International mRCC Database Consortium intermediate and high risk, diagnosed from January 2011 to December 2022, treated with first-line systemic therapies, and with histological documentation of the presence or absence of sarcomatoid features in nephrectomy specimens were identified using the Canadian Kidney Cancer information system (CKCis). In this study, treatment with immunotherapy was associated to an improved survival and response rates for mRCC patients with and without sarcomatoid features. The magnitude of benefit is increased in patients with sarcomatoid mRCC.

Evaluation of Volumetric Response Assessment From SABR for Renal Cell Carcinoma (RCC).

PURPOSE: SABR is increasingly used to treat renal cell carcinoma (RCC). However, the optimal method to assess treatment response is unclear. We aimed to quantify changes in both volume and maximum linear size of tumors after SABR and evaluate the utility of the 2 approaches in treatment response assessment. METHODS AND MATERIALS: We retrospectively studied patients with RCC treated with SABR at our institution between 2013 and 2020. All available follow-up computed tomography scans were aligned, and tumors were contoured on all scans. Volume and maximum linear size were measured at each follow-up, relative to these measurements at the time of computed tomography simulation. RESULTS: Twenty-four patients with 25 tumors were included. Median follow-up was 32 months (range, 16-67). Nineteen tumors (76%) had 30% volumetric response at a median time of 7 months after SABR, and 12 tumors (48%) had 30% decrease in maximum linear size at a median time of 16 months. Eighteen tumors (72%) decreased in volume on first follow-up scan and continued to shrink, and 5 tumors (20%) displayed transient growth after SABR (average 24% increase in volume). Compared with T1a tumors, T1b or larger tumors were more likely to have transient growth (8% vs 33%; P = .16) and had higher average relative volume 24 months after SABR (0.47 vs 0.8; P = .022). CONCLUSIONS: Volume measurement results in more pronounced and earlier change compared with linear size measurement when assessing response to SABR. These findings may provide guidance when assessing treatment response for patients with RCC treated with SABR.

18F-DCFPyL (PSMA) PET as a radiotherapy response assessment tool in metastatic prostate cancer.

Background: Prostate Specific Membrane Antigen (PSMA) - positron emission tomography (PET) guides metastasis-directed radiotherapy (MDRT) in prostate cancer (PrCa). However, its value as a treatment response assessment tool after MDRT remains unclear. Importantly, there is limited understanding of the potential of radiotherapy (RT) to alter PSMA gene (folate hydrolase 1; FOLH1) expression. Methodology: We reviewed a series of 11 men with oligo-metastatic PrCa (25 metastasis sites) treated with MDRT before re-staging with 18F-DCFPyL (PSMA) PET upon secondary recurrence. Acute effects of RT on PSMA protein and mRNA levels were examined with qPCR and immunoblotting in human wild-type androgen-sensitive (LNCap), castrate-resistant (22RV1) and castrate-resistant neuroendocrine (PC3 and DU145) PrCa cell lines. Xenograft tumors were analyzed with immunohistochemistry. Further, we examined PSMA expression in untreated and irradiated radio-resistant (RR) 22RV1 (22RV1-RR) and DU145 (DU145-RR) cells and xenografts selected for survival after high-dose RT. Results: The majority of MDRT-treated lesions showed lack of PSMA-PET/CT avidity, suggesting treatment response even after low biological effective dose (BED) MDRT. We observed similar high degree of heterogeneity of PSMA expression in both human specimens and in xenograft tumors. PSMA was highly expressed in LNCap and 22RV1 cells and tumors but not in the neuroendocrine PC3 and DU145 models. Single fraction RT caused detectable reduction in PSMA protein but not in mRNA levels in LNCap cells and did not significantly alter PSMA protein or mRNA levels in tissue culture or xenografts of the other cell lines. However, radio-resistant 22RV1-RR cells and tumors demonstrated marked decrease of PSMA transcript and protein expression over their parental counterparts. Conclusions: PSMA-PET may be a promising tool to assess RT response in oligo-metastatic PrCa. However, future systematic investigation of this concept should recognize the high degree of heterogeneity of PSMA expression within prostate tumors and the risk for loss of PSMA expression in tumor surviving curative courses of RT.

Differences in overall survival between clear cell metastatic renal cell carcinoma patients versus population-based controls according to race/ethnicity in the United States.

PURPOSE: To quantify differences in five-year overall survival (OS) between clear cell metastatic renal cell carcinoma (ccmRCC) patients and age- and sex-matched population-based controls, especially when race/ethnicity is considered. METHODS: We relied on the Surveillance, Epidemiology and End Results database (2006-2016) to identify newly diagnosed (2006- 2011) ccmRCC patients of either Caucasian, Hispanic, African American, or Asian/Pacific Islander race/ethnicity. For each case, we simulated an age- and sex-matched control (Monte Carlo simulation), relying on Social Security Administration Life Tables with five-year follow-up. We compared OS between ccmRCC patients and controls. Multivariable Cox regression models tested for race/ethnicity effect on OS. RESULTS: Of 3067 ccmRCC patients, 2167 (71%) were Caucasians vs. 488 (16%) Hispanics vs. 216 (7%) African Americans and 196 (6%) Asians/Pacific Islanders. At five years, OS difference between ccmRCC patients vs. population-based controls was greatest in African Americans (11 vs. 94%, Δ = 84%), followed by Hispanics (16 vs. 94%, Δ = 77%), Caucasians (16 vs. 89%, Δ = 73%) and Asians/Pacific Islanders (19 vs. 88%, Δ = 70%). In multivariable Cox regression models, African Americans exhibited highest Hazard Ratio for death (HR 1.3, p= 0.003). CONCLUSION: Relative to Life Tables' derived age- and sex-matched controls, ccmRCC patients exhibit drastically worse OS, especially African Americans.

Cost Effectiveness Analysis of Radiofrequency Ablation (RFA) Versus Stereotactic Body Radiotherapy (SBRT) for Early Stage Renal Cell Carcinoma (RCC).

OBJECTIVES: To conduct a cost-effectiveness analysis of stereotactic body radiotherapy (SBRT) versus radiofrequency ablation (RFA) in the non-surgical management of early stage renal cell carcinoma (RCC) according to Consolidated Health Economic Evaluation Reporting Standards (CHEERS) criteria in the Canadian healthcare system. METHODS: A Markov state transition model was constructed for initial local treatment with RFA or SBRT for early stage, kidney confined, medically inoperable RCC in a hypothetical cohort. Incremental cost effectiveness ratios (ICER) were then calculated to compare the two treatments. The analysis was conducted over 5-year time horizon from the perspective of a publicly funded health system in Canada. Secondary analyses were conducted to assess the effect of small versus large size (< 4 cm vs. > 4 cm) RCC on ICERs. Multiple one-way deterministic sensitivity analysis were conducted. Discounting of 1.5% per year was applied. RESULTS: Over 5 years, SBRT economically dominated RFA with a gain of 4.103 quality-adjusted life years (QALYs) and a cost of $16,097, compared with 3.607 QALYs at a cost of $18,324 for RFA. The ICER was $4490 CAD less per QALY for SBRT in the base case analysis (BCE). In patients with small tumors (T1a), SBRT compared with RFA was more effective and marginally more costly, resulting in an ICER of $2207 CAD per QALY gained, while for larger tumors (T1b), SBRT was less costly and more effective than RFA, resulting in an ICER of -$22904. Sensitivity analysis demonstrated significant variability in the cost-effectiveness of SBRT versus RFA when parameters were varied, with rates of distant metastasis following RFA or SBRT having the greatest implications on ICERs. CONCLUSION: Overall, SBRT used as a primary treatment for RCC shows promising effectiveness at an overall reduction in cost compared with RFA in the Canadian healthcare system. The use of SBRT appears to be cost-effective for larger tumors as well as smaller tumors. The validity of these conclusions are highly sensitive to the accuracy of local and distant progression rates reported in previous studies, and may be adjusted as the available data on SBRT and RFA continues to evolve and mature.

Development and initial validation of a cost-effective, re-usable, ultrasound-compatible suprapubic catheter insertion training simulator.

INTRODUCTION: Suprapubic catheterization (SPC) is a fundamental skill required of urology trainees. A lack of affordable simulation models and unpredictability of bedside SPCs limit experiential learning opportunities. Our objective was to develop and initially validate a re-usable, low-cost, ultrasound (US)-compatible SPC simulator for acquiring skills that transfer to the bedside. METHODS: The model was constructed using six components. Staff urologists and interventional radiologists (IRs) conducted a SPC and rated the model on three domains with multiple subcategories on a five-point Likert scale: anatomic realism; usefulness as a training tool; and global/overall reaction. Participants in our first-year urology "boot camp" received SPC training, practiced, and were evaluated via an objective structured clinical examination (OSCE). Staff ratings and OSCE scores determined the model's initial face and content validity. RESULTS: Twelve staff physicians participated in the study. The mean scores for urologists and IRs, respectively, were: anatomical realism: 4.10 and 3.70; usefulness as a training tool: 4.23 and 4.24; and overall reaction: 4.40 and 4.44. Staff strongly agreed that the model should be incorporated into the residency curriculum. Over the past four years, 25 boot camp participants scored a mean of 99.7% (±1.8) on the OSCE, with high technical performance and entrustment scores (4.8 and 4.7, respectively). The model cost $55 CAD. CONCLUSIONS: This novel, multiple-use, low-cost, easily reproducible US-compatible SPC simulator demonstrated initial face and content validity via high staff urologist and IR ratings and OSCE scores of first-year urology residents. Additional research is required for construct validation.

Faculty's perspective on skill assessment in undergraduate medical education: Qualitative online forum study.

BACKGROUND: India is at the nascent stage of competency-based medical education. Faculties trained in medical education are the main driving force for change. The present study explores the perception of faculties about the current practices and problems in medical/dental/nursing undergraduate assessment, barriers to adoption of best practices, and solutions for addressing them. METHODOLOGY: A qualitative study was designed and data collected through an asynchronous online discussion forum. A group of 31 health professionals (FAIMER fellows selected on the basis of active participation in department of medical education of respective colleges) participated in the forum. An open-ended topic guide with prompts was designed. The forum was initiated by release of discussion topics (threads) at the start of the month and remained in forum throughout the month. Researchers moderated and recorded day-to-day events. All online forum data were coded line by line and analyzed using conventional content analysis. RESULTS: Four categories generated were: (1) Low utility of current skill assessment system due to low validity and reliability; (2) Barrier in adopting newer assessment tool due to the absence of felt need of faculties and students, mistaken beliefs, and limited resources; (3) Poor implementation of newer assessment tools such as formatives and objective structured clinical examination with no blueprinting; and (4) Solutions proposed were regular formative assessment, criterion-based examination, quality-assured faculty development programs, and administrative support. CONCLUSIONS: Barriers in adopting newer assessment tools are related to the faculty's perception and resource constraint. This can be addressed by quality-assured faculty development programs and effective implementation of competency-based education.

Assessment of biochemical recurrence of prostate cancer (Review).

The assessment of the risk of biochemical recurrence (BCR) is critical in the management of males with prostate cancer (PC). Over the past decades, a comprehensive effort has been focusing on improving risk stratification; a variety of models have been constructed using PC­associated pathological features and molecular alterations occurring at the genome, protein and RNA level. Alterations in RNA expression (lncRNA, miRNA and mRNA) constitute the largest proportion of the biomarkers of BCR. In this article, we systemically review RNA­based BCR biomarkers reported in PubMed according to the PRISMA guidelines. Individual miRNAs, mRNAs, lncRNAs and multigene panels, including the commercially available signatures, Oncotype DX and Prolaris, will be discussed; details related to cohort size, hazard ratio and 95% confidence intervals will be provided. Mechanistically, these individual biomarkers affect multiple pathways critical to tumorigenesis and progression, including epithelial­mesenchymal transition (EMT), phosphatase and tensin homolog (PTEN), Wnt, growth factor receptor, cell proliferation, immune checkpoints and others. This variety in the mechanisms involved not only validates their associations with BCR, but also highlights the need for the coverage of multiple pathways in order to effectively stratify the risk of BCR. Updates of novel biomarkers and their mechanistic insights are considered, which suggests new avenues to pursue in the prediction of BCR. Additionally, the management of patients with BCR and the potential utility of the stratification of the risk of BCR in salvage treatment decision making for these patients are briefly covered. Limitations will also be discussed.

Symptom assessment to guide treatment selection and determine progression in metastatic castration-resistant prostate cancer: Expert opinion and review of the evidence.

Multiple new agents to treat metastatic castration-resistant prostate cancer (mCRPC) have become available in recent years; however, the appropriate timing and sequencing of these agents have yet to be elucidated. Until accurate biomarkers become available to allow more focused therapeutic targeting for this population, treatment selection for men with mCRPC will continue to be driven largely by close assessment of patient-related factors and symptoms. Pain, as the predominant symptom of mCRPC, is often the focus when assessing progression and the need for a change in treatment. A myriad of other symptoms, including fatigue, impact on activities of daily living, sleep, and lower urinary tract symptoms, also affect men with mCRPC, and assessment of the composite of these symptoms provides an earlier signal for the need to adjust treatment. A number of tools are available for assessing symptoms in patients with advanced prostate cancer, but they are not routinely used, given their complexity and length. A new simplified questionnaire is proposed for the assessment of symptoms, beyond pain, to inform treatment decisions for men with mCRPC.

Cost-utility of Sunitinib Versus Pazopanib in Metastatic Renal Cell Carcinoma in Canada using Real-world Evidence.

BACKGROUND AND OBJECTIVE: The development of new targeted therapies in kidney cancer has shaped disease management in the metastatic phase. Our study aims to conduct a cost-utility analysis of sunitinib versus pazopanib in first-line setting in Canada for metastatic renal cell carcinoma (mRCC) patients using real-world data. METHODS: A Markov model with Monte-Carlo microsimulations was developed to estimate the clinical and economic outcomes of patients treated in first-line with sunitinib versus pazopanib. Transition probabilities were estimated using observational data from a Canadian database where real-life clinical practice was captured. The costs of therapies, disease progression, and management of adverse events were included in the model in Canadian dollars ($Can). Utility and disutility values were included for each health state. Incremental cost-utility ratio (ICUR) and incremental cost-effectiveness ratios (ICER) were calculated for a time horizon of 5 years, from the Canadian Healthcare System perspective. RESULTS: The cost difference was $36,303 and the difference in quality-adjusted life year (QALY) was 0.54 in favour of sunitinib with an ICUR of $67,227/QALY for sunitinib versus pazopanib. The major cost component (56%) is related to best supportive care (BSC) where patients tend to stay for a longer period of time compared to other states. The difference in life years gained (LYG) between sunitinib and pazopanib was 1.21 LYG (33.51 vs 19.03 months) and the ICER was $30,002/LYG. Sensitivity analysis demonstrated the robustness of the model with a high probability of sunitinib being a cost-effective option when compared to pazopanib. CONCLUSION: When using real-world evidence, sunitinib is found to be a cost-effective treatment compared to pazopanib in mRCC patients in Canada.

Adjuvant chemotherapy for upper-tract urothelial carcinoma treated with nephroureterectomy: assessment of adequate renal function and influence on outcome.

OBJECTIVES: Upper-tract urothelial carcinoma (UTUC) is associated with poor outcomes. Our aim was to assess adequacy of renal function and evaluate the role of adjuvant chemotherapy (AC) in patients with UTUC treated by radical nephroureterectomy (RNU) in a universal health care system. MATERIALS AND METHODS: Retrospective data from 1,029 patients treated with RNU across 10 Canadian academic centers were collected. Tested variables included various clinico-pathological parameters, the use of perioperative chemotherapy, preoperative and postoperative creatinine values, and estimated glomerular filtration rates (eGFR). Univariable and multivariable Cox regression models addressed overall survival and disease-specific survival after surgery. Kaplan-Meier survival curves were used to compare outcomes in patients who received or did not receive AC. RESULTS: Median age of patients was 70 years with a median follow-up of patients who were alive of 26 months. The median preoperative and postoperative eGFR rates were 59 mL/min/1.73 m(2) and 47 mL/min/1.73 m(2), respectively. Using a cutoff eGFR of 60, 49% of all the patients and 48% of the patients with ≥ pT3 or pTxN+ or both diseases would have been eligible for cisplatin-based chemotherapy preoperatively and only 18% and 21% of the patients, respectively remained eligible postoperatively. Of the patients who received AC, 75% had an eGFR<60. On multivariate analysis, AC was not prognostic for improved overall survival or disease-specific survival. CONCLUSIONS: Chronic kidney disease is common in patients with UTUC. Following RNU, 57% of the high-risk patients with good preoperative renal function became ineligible for cisplatin-based chemotherapy. Use of AC did not translate into improved survival. Whether this is due to inherent biases of retrospective analysis, limited efficacy of AC in patients with UTUC, or use of suboptimal regimen or dose because of poor postoperative renal function requires further evaluation.

Cost-utility analysis of radical nephrectomy versus partial nephrectomy in the management of small renal masses: Adjusting for the burden of ensuing chronic kidney disease.

OBJECTIVES: We compare the cost-utility of laparoscopic radical nephrectomy (LRN), laparoscopic partial nephrectomy (LPN) and open partial nephrectomy (OPN) in the management of small renal masses (SRMs) when the impact of ensuing chronic kidney disease (CKD) disease is considered. METHODS: We designed a Markov decision analysis model with a 10-year time horizon. Estimates of costs, utilities, complication rates and probabilities of developing CKD were derived from the literature. The base case patient was assumed to be a 65-year-old patient with a <4-cm unilateral renal mass, a normal contralateral kidney and a normal preoperative serum creatinine. Univariate and probabilistic sensitivity analyses were conducted to address the uncertainty associated with the study parameters. RESULTS: OPN was the least costly strategy at $25 941 USD and generated 7.161 quality-adjusted life years (QALYs) over 10 years. LPN yielded 0.098 additional QALYs at an additional cost of $888 for an incremental cost-effectiveness ratio of $9057 per QALY, well below a commonly cited willingness-to-pay threshold of $50 000 per QALY. LRN was more costly and yielded fewer QALYs than OPN and LPN. Sensitivity analyses demonstrated our model to be robust to changes to key parameters. Age had no effect on preferred strategy. CONCLUSIONS: Partial nephrectomy (PN) is the preferred treatment strategy for SRMs. In centres where LPN is not available, OPN remains considerably more cost-effective than LRN. Furthermore, our study demonstrates that there is no age at which PN is not preferred to LRN. Our study provides additional evidence to advocate PN for the management of all amenable SRMs.

Obesity and renal cell carcinoma: epidemiology, underlying mechanisms and management considerations.

The incidence of both renal cell carcinoma (RCC) and obesity are steadily rising in Western societies. Recent studies have established that obesity is a significant risk factor for the development of several malignancies, including RCC. However, the mechanisms underlying this relationship remain to be fully elucidated. We review herein the epidemiological links between obesity and RCC, the potential mechanisms by which obesity can influence RCC development and progression, and the special considerations related to the treatment of obese patients with RCC.

Laparoscopic versus open partial nephrectomy.

OBJECTIVES: To compare, retrospectively, the results of laparoscopic partial nephrectomy (LPN) to open partial nephrectomy (OPN) using a tumor size-matched cohort of patients. Limited data are available comparing LPN to OPN in the treatment of small renal tumors. METHODS: Between September 2000 and September 2003, 27 LPNs and 22 OPNs were performed to treat renal masses less than 4 cm. Patient demographics and tumor location and size (2.4 +/- 1.0 cm versus 2.9 +/- 0.9 cm, respectively; P = not statistically significant) were similar between the LPN and OPN groups. RESULTS: Although the mean operative time was longer in the LPN than in the OPN group (210 +/- 76 minutes versus 144 +/- 24 minutes; P <0.001), the blood loss was comparable between the two groups (250 +/- 250 mL versus 334 +/- 343 mL; P = not statistically significant). No blood transfusions were performed in either group. The hospital stay was significantly reduced after LPN compared with after OPN (2.9 +/- 1.5 days versus 6.4 +/- 1.8 days; P <0.0002), and the postoperative parenteral narcotic requirements were lower in the LPN group (mean morphine equivalent 43 +/- 62 mg versus 187 +/- 71 mg; P <0.02). Three complications occurred in each group. With LPN, no patient had positive margins or tumor recurrence. Also, direct financial analysis demonstrated lower total hospital costs after LPN (4839 dollars+/- 1551 dollars versus 6297 dollars+/- 2972 dollars; P <0.05). CONCLUSIONS: LPN confers several benefits over OPN concerning patient convalescence and costs, despite prolonged resection times at our current phase of the learning curve. Long-term results on cancer control in patients treated with LPN continue to be assessed.