Systemic agents including immune checkpoint inhibitors, antibody-drug conjugates, and targeted therapies play a critical role in the management of bladder cancer. Novel localized delivery mechanisms for existing systemic agents explore solutions to improve treatment response without compromising safety. Herein, we review the contemporary innovations in modern intravesical agents, hyperthermic drug delivery, reverse-thermal gels, nanocarriers, gene therapy, and subcutaneous therapies.

Non-muscle invasive bladder cancer (NMIBC) is a common and burdensome malignancy. A substantial proportion of patients with intermediate- and high-risk disease will progress to invasive bladder cancer and are at a significant risk for metastasis and death. Bacillus Calmette-Guerin (BCG) therapy for selected cases has been the standard of care for nearly 40 years. Unfortunately, a world-wide shortage has made BCG challenging to obtain. Furthermore, recurrences and progressions do occur. With the US Food and Drug Administration creating a clear path to drug approval for novel treatments, many therapies have been tested, including intravesical cytotoxic chemotherapy, intravesical immunotherapy, systemic immunotherapy, and novel agents, such as gene therapy and targeted therapy. In this review, we highlight ongoing clinical trials.

Our expanding knowledge of immunotherapy for solid tumors has led to an explosion of clinical trials aimed at urothelial carcinoma. The primary strategy is centered on unleashing the immune system by releasing the inhibitory signals propagated by programmed cell death-1 (PD-1) and its ligand programmed cell death ligand-1 (PD-L1). Many antibody constructs have been developed to block these interactions and are used in clinical trials. The Food and Drug Administration has already approved a number of checkpoint inhibitors such as anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) monoclonal antibodies including ipilimumab; anti-PD-1 monoclonal antibodies including nivolumab and pembrolizumab; anti-PD-L1 antibodies including atezolizumab, avelumab, and durvalumab. One of the latest inhibitors is durvalumab, which is a high-affinity human immunoglobulin G1 kappa monoclonal antibody and blocks the interaction of PD-L1 with PD-1 and CD80. Currently, there are a number of ongoing trials in advanced urothelial carcinoma both using durvalumab monotherapy and in combination with other targeted therapies. In addition, durvalumab is being investigated in the non-muscle-invasive urothelial carcinoma, which is centered around intravenous formulations. These exciting developments have added a significant number of therapies in a previously limited treatment landscape.

Background

Beyond age and comorbidity, functionality can shape the long-term survival potential of patients with cancer. Accordingly, herein the authors compared mortality and receipt of cancer-directed surgery according to patient function among older adults with kidney cancer.

Methods

Using Surveillance, Epidemiology, and End Results (SEER)-Medicare data from 2000 through 2009, the authors studied 28,326 elderly subjects with primary kidney cancer. Patient function was quantified using function-related indicators, claims indicative of dysfunction and disability. Adjusting for patient and cancer characteristics, competing risk regression was used to assess the relationship between function-related indicator count and cause-specific mortality and then generalized estimating equations were used to quantify the probability of surgery.

Results

A total of 13,619 adult patients (48.1%) with at least 1 function-related indicator were identified. A higher indicator category was associated with older age, greater comorbidity, female sex, unmarried status, lower socioeconomic status, and higher stage of disease (P<.001). Compared with patients with an indicator count of 0, those with an indicator count of 1 (hazard ratio, 1.10; 95% confidence interval [95% CI], 1.04-1.16) and ≥2 (hazard ratio, 1.46; 95% CI, 1.39-1.53) were found to have higher other-cause mortality. Conversely, kidney cancer mortality varied minimally with patient function. Patients with ≥ 2 indicators received cancer-directed surgery less often than those without disability (odds ratio, 0.61; 95% CI, 0.56-0.66), although treatment probabilities remained high for patients with locoregional disease and low for those with metastatic cancer.

Conclusions

Among older adults with kidney cancer, functional health stands as a significant predictor of long-term survival. However, receipt of cancer-directed surgery appears largely determined by cancer stage. Patient function should be considered more heavily when determining treatment for older adults with kidney cancer. Cancer 2016;122:3776-3784. © 2016 American Cancer Society.

Introduction

Intravesical bacillus Calmette-Guérin (BCG) therapy is the gold standard adjuvant treatment for patients with high-grade non-muscle-invasive bladder cancer (NMIBC). Despite the association between metabolic syndrome (MetS) and bladder cancer, the association between MetS and BCG failure is unknown. The objective of this study was to characterize disease recurrence following BCG in patients with and without MetS.

Methods

We retrospectively evaluated the records of patients undergoing TURBT at our institution in 2012-2015 for NMIBC and identified those who received adjuvant BCG therapy. MetS was defined as having three of four components: diabetes mellitus, hyperlipidemia, hypertension, or body mass index (BMI)≥30kg/m². The primary outcome was recurrence or progression. Descriptive statistics, chi-squared analysis, Kaplan-Meier survival analysis, and Cox multivariable regression analyses were performed.

Results

High grade was present in 83/90 (92.2%) patients. MetS was present in 27/90 (30%) patients. Median follow-up was 20 months. On Kaplan-Meier analysis, patients with MetS had worse DFS compared with patient without MetS. On multivariable analysis, BMI≥30 kg/m² was a significant predictor of recurrence or progression (HR 2.94, 95% CI: 1.43-6.03). Presence of MetS did not significantly affect the type of BCG failure.

Conclusions

The association between MetS and failure to respond to BCG therapy is multifactorial but is in part associated with obesity. Elevated BMI is strongly associated with recurrence or progression. Further studies are warranted to investigate the relationship between increased adiposity and response to BCG, especially as other novel immunotherapeutic agents are likely to enter the NMIBC space.

Background

Intravesical Mitomycin-C (MMC) following transurethral resection of bladder tumor (TURBT), while efficacious, is associated with side effects and poor utilization. Continuous saline bladder irrigation (CSBI) has been examined as an alternative. In this study we sought to compare the rates of recurrence and/or progression in patients with NMIBC who were treated with either MMC or CSBI after TURBT.

Methods

We retrospectively reviewed records of patients with NMIBC at our institution in 2012-2015. Perioperative use of MMC (40 mg in 20 mL), CSBI (two hours), or neither were recorded. Primary outcome was time to recurrence or progression. Descriptive statistics, chi-squared analysis, Kaplan-Meier survival analysis, and Cox multivariable regression analyses were performed.

Results

205 patients met inclusion criteria. Forty-five (22.0%) patients received CSBI, 71 (34.6%) received MMC, and 89 (43.4%) received no perioperative therapy. On survival analysis, MMC was associated with improved DFS compared with CSBI (p = 0.001) and no treatment (p = 0.0009). On multivariable analysis, high risk disease was associated with increased risk of recurrence or progression (HR 2.77, 95% CI: 1.28-6.01), whereas adjuvant therapy (HR 0.35, 95% CI: 0.20-0.59) and MMC (HR 0.43, 95% CI: 0.25-0.75) were associated with decreased risk.

Conclusions

Postoperative MMC was associated with improved DFS compared with CSBI and no treatment. The DFS benefit seen with CSBI in other studies may be limited to patients receiving prolonged irrigation. New intravesical agents being evaluated may consider saline as a control given our data demonstrating that short-term CSBI is not superior to TURBT alone.

Objectives

To characterize the extent to which geriatric and related healthcare services are provided to older adults undergoing surgery for kidney cancer, a potential growth area in geriatrics and oncology.

Design

Population-based observational study.

Setting

Surveillance, Epidemiology, and End Results cancer data linked with Medicare claims.

Participants

Adults aged 65 and older with kidney cancer treated surgically from 2000 to 2009 (N = 19,129).

Measurements

Receipt of geriatric consultation, medical comanagement during the surgical hospitalization, inpatient physical or occupational therapy (PT/OT), and postacute PT/OT during the surgical care episode. Multivariable, mixed-effects models were used to identify associated participant and hospital characteristics, examine trends over time, and characterize hospital-level variation.

Results

Geriatric consultation occurred rarely in the perioperative period (2.6%). Medical comanagement (15.8%), inpatient PT/OT (34.2%), and postacute PT/OT (15.6%) occurred more frequently. In our mixed-effects models, participant age and comorbidity burden appeared to be consistent determinants of use of services, although hospital-level variation was also noted (P < .001). Use of geriatric consultation increased modestly in the latter years of the study period (P < .05). In contrast, medical comanagement (183%), inpatient PT/OT (73%), and postacute PT/OT (71%) increased substantially over the study period (P < .001).

Conclusion

Although geriatric consultation remained sparse, use of medical comanagement and rehabilitation services has grown considerably for older adults undergoing surgery for kidney cancer. Efforts to reorganize cancer and surgery care should explore reasons for variation and the potential for these service elements to meet the health needs of an aging population.

Men with high-grade prostate cancer (HGPC) are at greatest risk of disease progression. Clinical risk factors associated with castration-resistant prostate cancer (CRPC), metastases, and prostate cancer-specific mortality (PCSM) were identified in a contemporary HGPC cohort. Clinical data was collected from men diagnosed with Gleason sum (GS) ≥8 at the Greater Los Angeles Veterans Affairs (GLA-VA) Healthcare System between 2000 and 2013. Multivariable competing risks regression analyses assessed progression to CRPC, metastases, and PCSM within three treatment strata. The cumulative incidence of disease progression was calculated at 2, 5, and 10-year time points. Review of 2149 prostate cancer cases yielded 322 with HGPC. Median survival times for cancer-specific and overall mortality were significantly shorter in men treated with primary androgen deprivation therapy (ADT) (P = 0.0002 and P < 0.0001). Multivariable analyses revealed that clinical stage N1, GS 10, and treatment with primary ADT were significantly associated with increased risk of CRPC, metastases, and PCSM. Significant differences in these outcomes were not observed in men treated with radical prostatectomy (RP) when compared to those treated with radiation therapy combined with short-term ADT (XRT-ADT). Ten-year event rates of progression to CRPC, metastases, and PCSM, for men treated with primary ADT, were 45.5%, 25.4%, and 25.1%, respectively. In conclusion, GS 10 and lymph node involvement, as well as primary ADT treatment in men with HGPC was associated with increased risk of CRPC, metastases, and PCSM. Curative-intent treatment with RP or XRT-ADT is associated with reduced progression rates and death in men with HGPC.

Penile fracture (PF) is a surgical emergency. Given its rarity, we queried a national cohort over an 11-year period to study the temporal and demographic variations in presentation, evaluation, and management of patients with PF compared with a cohort of control patients. The National Inpatient Sample was queried between the years 2005 and 2016 for patients with a diagnosis of PF. Appendectomy patients were selected as a control cohort, given the non-discriminatory nature of this disease. Clinical and demographic data of the patients were compared with that of controls. Presenting symptoms, rates of surgical repair, and rates of associated surgical procedures were evaluated in the PF cohort. During the study period, 5802 patients were hospitalized for PF. The annual incidence of PF remained unchanged at 1.0-1.8 cases per 100 000 hospitalizations over the study period. Compared with the control cohort, PF patients were more likely to be younger (38.7 years vs 41.2 years, P ≤ 0.001), have lower rates of comorbidities except erectile dysfunction (1.4% vs 0.1%, P ≤ 0.001), and were more likely of Black race (25.4% vs 6.2%, P ≤ 0.001). Notably, PF patients had significantly higher rates of substance abuse (26.4% vs 18.1%, P ≤ 0.001), despite no difference in the diagnosed psychiatric disorders. PF rarely presented with hematuria (3.5%); however, urethral evaluation was performed in 23.1%, most commonly with cystoscopy (19.2%). PF occurs more commonly in a younger, healthier male population, and among minorities. Importantly, rates of substance abuse appear to be higher in the PF cohort compared with those of controls.

Postoperative ileus (POI) and constipation are common secondary effects of opioids and carry significant clinical and economic impacts. μ-Opioid receptors mediate opioid analgesia in the central nervous system (CNS) and gastrointestinal-related effects in the periphery. Peripherally acting μ-opioid receptor antagonists (PAMORAs) block the peripheral effects of opioids in the gastrointestinal tract, while maintaining opioid analgesia in the CNS. While most are not approved for POI or postoperative opioid-induced constipation (OIC), PAMORAs have a potential role in these settings via their selective effects on the μ-opioid receptor. This review will discuss recent clinical trials evaluating the safety and efficacy of PAMORAs, with a focus on alvimopan (Entereg^®) and methylnaltrexone (Relistor^®) in patients with POI or postoperative OIC. We will characterize potential factors that may have impacted the efficacy observed in phase 3 trials and discuss future directions for the management and treatment of POI.