The Pros and Cons of “Machination of Medicine” in Genitourinary Practice
ABSTRACT:
The increasing availability of genomic sequencing of tumor tissue in oncology provided valuable insights into tumor evolution and offered clinicians the unprecedented opportunity to tailor therapies on each individual patient, according to the treatment-impacting alterations identified in the tumor cells. In addition to the characterization of somatic alterations in tumor samples, the identification of germline (i.e., constitutional) pathogenic variants can provide additional information to guide informed and personalized therapeutic planning for patients and to enable risk-based screening protocols for at-risk relatives. In genitourinary malignancies, only a few associations between germline mutations and cancer risk and behavior have been thoroughly investigated (e.g., alterations in DNA repair genes in prostate cancer or mutations in Lynch syndrome genes in upper tract urothelial carcinoma). To achieve a wider use of both tumor genomic and germline genetic testing, an integrative approach led by scientific societies is necessary to involve physicians, patients and advocacy groups, to develop a shared strategy to advance the field and provide value-based and reproducible standards of care for patients and their families.
CD274 (PD-L1) Copy Number Changes (Gain) & Response to Immune Checkpoint Blockade Therapy in Carcinomas of the Urinary Tract
ABSTRACT:
BACKGROUND:
Immune checkpoint inhibitors are an important therapeutic option for urothelial carcinoma, but durable responses are achieved in a minority of patients. Identifying pre-treatment biomarkers that may predict response to these therapies or who exhibit intrinsic resistance, is of paramount importance.
OBJECTIVE:
To explore the prevalence of PD-L1 copy number alteration in urothelial carcinoma and correlate with response to immune checkpoint inhibitors.
METHODS:
We analyzed a cohort of 1050 carcinomas of the bladder and upper urinary tract that underwent targeted next generation sequencing, prospectively. We assessed PD-L1 protein expression, copy number status (next generation sequencing/FISH), and detailed treatment response.
RESULTS:
We identified 9 tumors with PD-L1 amplification and 9 tumors with PD-L1 deletion. PD-L1 protein expression was the highest in PD-L1 amplified tumors. Of the 9 patients whose tumors harbored PD-L1 amplification, 6 received immunotherapy with 4 deriving clinical benefit, and 2 achieving durable response. Of the 9 patients whose tumors had PD-L1 copy number losses, 4 received immunotherapy with 3 experiencing disease progression.
CONCLUSIONS:
PD-L1 copy number alterations may serve as potential biomarkers of response to immunotherapy in urothelial carcinoma patients, if validated in larger cohorts.
Impact of Neoadjuvant Chemotherapy for Upper Tract Urothelial Carcinoma: A Population Based Analysis
ABSTRACT:
BACKGROUND AND OBJECTIVES:
We examined pathologic complete response (pCR) and pathologic downstaging (pDS) rates after neoadjuvant chemotherapy (NAC) in high-risk upper tract urothelial carcinoma, as well as their predictors. We further sought to determine their effects on overall survival and examine prognosticators of survival after NAC.
METHODS:
The National Cancer Database was used to identify all patients from 2004 to 2016 with nonmetastatic high grade upper tract urothelial carcinoma who received NAC followed by nephroureterectomy. pCR and pDS rates were examined, and univariate and multivariate logistic regression was performed to identify clinical predictors. Kaplan-Meier and Cox proportional hazard methods were used to estimate overall survival.
309 patients met inclusion criteria. 27 patients (8.74%) had pCR, and 92 (29.77%) had pDS. pCR and pDS rates for N+ subgroup were 6.82% and 47.73% respectively, and for N0 subgroup, 9.50% and 22.62%. Female sex (OR 2.94, p = 0.010) was the only predictor of pCR. Node-positive disease (cN1 vs. cN0: OR 6.40, p < 0.001; cN2 vs. cN0: OR 7.46, p < 0.001) was a positive predictor of pDS, and the presence of lymphovascular invasion (LVI) (OR 0.14, p < 0.001) was a negative predictor of pDS. The median OS for all patients was 45.5 months. pCR and pDS were both associated with improved OS, (p < 0.001 for both); median was 99.1 months for both. LVI was the strongest negative prognostic factor for OS (HR 2.85, p < 0.001).
Overall pathological complete response and downstaging rates were 8.74% and 29.77% respectively after multi-agent neoadjuvant chemotherapy. Node-negative and node-positive disease had equivalent rates of complete response, but node-positive disease had a significantly higher rate of downstaging. The presence of LVI was associated with worse overall survival.
Real-World Study of Treatment with Pembrolizumab Among Patients with Advanced Urothelial Tract Cancer in Denmark
ABSTRACT:
BACKGROUND:
Investigating the effect of newly approved oncological drugs in the real-world is warranted. With emerging novel treatments rapidly being approved for urothelial tract cancers, we aimed to assess real-world data, regarding effect and safety, during the first year after approval of pembrolizumab in Denmark for patients with locally advanced and unresectable or metastatic urothelial tract cancer (mUTC) in the first- and second-line setting.
MATERIALS AND METHODS:
At the six oncological departments treating mUTC in Denmark, we identified all mUTC patients receiving pembrolizumab during the first year after approval, between March 1, 2018 and February 28, 2019. A retrospective data collection was conducted from January to June 2020. Patient characteristics matching that of the relevant clinical trials for pembrolizumab in first- and second-line treatment-setting, overall survival (OS), progression-free survival (PFS), toxicity and tumor response were assessed.
139 patients were identified, 53 in first-line treatment, 77 in second-line, and 9 receiving third or later lines of treatment. The population was characterized by a majority of males (70%), most patients had ECOG PS 0–1 (60.4%) and primary tumor in the bladder was predominant (90.6%). The overall response rate (ORR) in first-line was 30.2%, PFS was 3,5 months (95%CI 2,3–7,9 months) and OS 9,2 months (95%CI 7,0–20.9 months). For second-line treatment the ORR was 27,3%, PFS 2,9 months (95%CI 2,5–5,3) and OS 9.1 months (95%CI 5,4–12,8 months). Toxicity was comparable to clinical trials without any new toxicities registered.
Real-world data on response rates, OS, PFS and toxicity for patients with mUTC receiving pembrolizumab in first- and second-line, shows comparable results to clinical trials. This study further establishes immunotherapy as an effective and tolerable treatment for mUTC.
Safety and Pharmacokinetics of Intravesical Chitosan/Interleukin-12 Immunotherapy in Murine Bladders
ABSTRACT:
BACKGROUND:
Intravesical administration of interleukin 12 (IL-12) co-formulated with the biopolymer, chitosan (CS/IL-12), has demonstrated remarkable antitumor activity against preclinical models of bladder cancer. However, given historical concerns regarding severe toxicities associated with systemic IL-12 administration in clinical trials, it is important to evaluate the safety of intravesical CS/IL-12 prior to clinical translation.
OBJECTIVE:
To evaluate the pharmacokinetics as well as the local and systemic toxicities of intravesical CS/IL-12 immunotherapy in laboratory mice.
METHODS:
Local inflammatory responses in mouse bladders treated with intravesical IL-12 or CS/IL-12 were assessed via histopathology. Serum cytokine levels following intravesical and subcutaneous (s.c.) administrations of IL-12 or CS/IL-12 in laboratory mice were compared. Systemic toxicities were evaluated via body weight and liver enzyme levels.
Intravesical IL-12 and CS/IL-12 treatments did not induce significant local or systemic toxicity. IL-12 dissemination and exposure from intravesical administration was significantly lower compared to s.c. injections. Weekly intravesical CS/IL-12 treatments were well-tolerated and did not result in blunted immune responses.
Intravesical CS/IL-12 is safe and well-tolerated in mice. In particular, the lack of cystitis and acute inflammation justifies continued investigation of intravesical CS/IL-12 immunotherapy in larger animals and patients with bladder cancer.
Cost of Care in Open Cystectomy Patients Across Time and Space: Does it Matter?
ABSTRACT:
BACKGROUND:
Many variables may affect the cost of open radical cystectomy (RC) care, including surgical approach, diversion type, patient comorbidities, and postoperative complications.
OBJECTIVE:
To determine factors associated with changes in cost of care following open radical cystectomy (ORC) for bladder cancer using the National Inpatient Sample (NIS).
METHODS:
Patients in the NIS with a diagnosis of bladder cancer who underwent ORC with ileal conduit from 2012–2017 using ICD-9-CM and ICD-10-CM codes were identified. Baseline demographics including age, race, region, postoperative complications, and length of stay were obtained. Univariable and multivariable logistic regression were used to identify factors associated with cost variation including demographics, clinical characteristics, surgical factors, and discharge quarter (Q1-Q4).
5,189 patients were included in the analysis, with 4,379 at urban teaching hospitals. On multivariable regression analysis, female sex [$1,734 ($1,024–2,444) p < 0.001)], a greater Elixhauser comorbidity score [$93 ($62–124), p < 0.001], presence of any inpatient complication [$1,531 ($894–2,168), p < 0.001], and greater length of stay [$1,665 ($1,536–1,793), p < 0.001] were associated with a greater cost of hospitalization. Discharge in Q3 (July to September) relative to Q2 (April to June) was associated with a higher cost [$1,113 ($292–1,933), p = 0.008. Trends were similar at urban non-teaching and rural hospitals, except discharge quarter was not associated with a significant change in cost.
Significant differences in cost of ORC with ileal conduit exist with respect to patient sex, medical comorbidities, and discharge timing. These differences may relate to greater disease burden in female patients, patient complexity, and variation in postoperative care in academic programs.
Optimizing Nutritional Status in Patients Undergoing Radical Cystectomy: A Systematic Scoping Review
ABSTRACT:
BACKGROUND:
Nutrition is a modifiable risk factor for patients undergoing multimodal oncologic interventions and plays a major supportive role in the setting of bladder cancer. For patients undergoing radical cystectomy (RC), malnutrition is associated with increased postoperative complications and mortality.
OBJECTIVE:
The purpose of this scoping review is to characterize the role of nutritional interventions for patients undergoing RC for bladder cancer.
METHODS:
A multi-database systematic scoping review based on the Preferred Reporting Items for Systematic Reviews extension for Scoping Reviews (PRISMA-ScR) guidelines was performed. Search terms were developed a priori to identify clinical trials that focused on nutritional interventions for patients with bladder cancer undergoing RC. Eligible articles were original research articles or abstracts from clinical trials evaluating nutritional interventions in adult patients undergoing RC. Articles were excluded if they did not focus on a nutritional intervention, if patients did not carry a diagnosis of bladder cancer, or if RC was not performed. Articles were reviewed independently by the authors, and inclusion/exclusion were based on consensus agreement.
A total of 83 articles were identified, of which 17 were included in the final analysis. A total of 49 articles were excluded during abstract screening. An additional 17 articles were excluded based on the review of full-text articles. Results of the scoping review suggest that data on the use of nutritional screening, assessment, and intervention for patients undergoing RC are scarce. Although parenteral nutrition (PN) appears to be associated with greater complications after RC, early introduction of food postoperatively or feeding enterally offers benefit and immunonutrition supplements with a focus on a high protein diet have the potential to better optimize surgical outcomes.
Although the prevalence and consequences of malnutrition among patients undergoing RC are well-established, there are limited data evaluating the use of nutritional screening, assessment, and interventions for this population. The pursuit of future clinical trials in this space is critical.
Quality of Life Following Chemoradiotherapy for Localized Muscle Invasive Bladder Carcinoma: A Systematic Review
ABSTRACT:
BACKGROUND:
Health Related Quality of Life (HRQoL) is an important factor regarding treatment for localized Muscle Invasive Bladder Carcinoma (MIBC), as it may affect choice of treatment. The impact of chemoradiotherapy (CRT) for MIBC on HRQoL has not yet been well-established.
OBJECTIVE:
To systematically evaluate evidence regarding HRQoL as assessed by validated questionnaires after definitive treatment with CRT for localized MIBC.
METHODS:
We performed a critical review of PubMed/MEDLINE, EMBASE, and the Cochrane Library in October 2020. Two reviewers independently screened articles for eligibility and assessed the methodological quality of the included articles using Joanna Briggs Institute critical appraisal tools. A narrative synthesis was undertaken.
Of 579 articles identified, 11 studies were eligible for inclusion, including three RCTs and 8 non-randomized studies, reporting on HRQoL data for 606 CRT patients. Global health declined at End of Treatment (EoT), and recovered 3 months following treatment. Physical function declined from baseline at EoT and recovered between 3 and 24 months and was maintained at 5 years follow up. CRT had little effect on social and emotional function in the short-term, but HRQoL results in the long-term were lower compared to the general population. Urinary function declined from baseline at EoT, but returned to baseline at 6 months following CRT. After initial decline in bowel function, a complete return to baseline occurred 4 years following treatment. The majority of studies assessing sexual function showed no to little effect on sexual function.