Telehealth Is a Sustainable Population Health Strategy to Lower Costs and Increase Quality of Health Care in Rural Utah.

PURPOSE: A telehealth oncology practice was created to care for patients in rural communities to improve access to health care, decrease financial burdens, and save time. PATIENTS AND METHODS: Patients with cancer at Sevier Valley Hospital in Richfield, Utah, were treated with a real-time video-based telehealth program under the care of an oncologist at a tertiary medical center. Data on financial savings, travel hours, mileage avoided, carbon emissions reduced, and revenue retained by Sevier Valley Hospital were collected from 2015 to 2018. RESULTS: From 2015 to 2018, 119 patients with cancer in Richfield, Utah, were treated with telehealth for oncology visits, accounting for 1,025 patient encounters. On average, patients saved 4 hours and 40 minutes and 332 miles roundtrip per encounter. In total, patients' savings were estimated to be $333,074. Carbon emissions were reduced by approximately 150,000 kg. Of new patient referrals, 59% were for solid tumors (70 of 119 referrals; 42 metastatic and 28 nonmetastatic cancers), and 41% were hematology consultations (49 of 119 referrals; 28 classical and 21 malignant hematologic conditions). We estimate that Sevier Valley Hospital retained $3,605,500 in revenue over this 4-year period. CONCLUSION: Using a telehealth program in rural Utah, patients with cancer benefited from substantial time and monetary savings. The local medical center was able to retain revenue it would have otherwise lost to outsourcing cancer care. Recent regulatory changes to address the COVID-19 pandemic should increase the number of patients with cancer treated via telehealth nationwide.

Time from definitive therapy to onset of metastatic disease predicts outcomes in men with metastatic hormone sensitive prostate cancer.

PURPOSE: Contemporary treatment for metastatic hormone sensitive prostate cancer (mHSPC) includes androgen deprivation therapy (ADT) plus abiraterone or docetaxel. While these intensified regimens have improved efficacy, they are also associated with increased cost and toxicities. Not all men with mHSPC may be candidates for these intensified regimens, yet there are no clinical models or biomarkers used to optimize treatment selection. Herein, we hypothesized that longer time from prior definitive therapy (DT), either radical prostatectomy, definitive radiotherapy, or both, to onset of metastatic disease is associated with improved survival outcomes in men with newly diagnosed mHSPC. METHODS: This multicenter retrospective study included men initiating systemic therapy with ADT for new mHSPC. Kaplan-Meier and COX proportional hazard models assessed time to metastatic castration-resistant prostate cancer (mCRPC) and overall survival (OS) by receipt of prior DT. RESULTS: Of the 253 men with new mHSPC, 115 (45%) had received prior DT. In a multivariate analysis, increasing years from DT to the start of ADT was an independent predictor of time to mCRPC (per year: hazard ratio 0.91 95% confidence interval 0.84-0.99, P = 0.020) and improved OS (per year: hazard ratio 0.87, 95% confidence interval 0.74-0.99, P = 0.0025) in patients with new mHSPC, and may assist with risk stratification in these patients at time of mHSPC. CONCLUSION: Time from DT to start of ADT is an independent predictor of time to mCRPC and OS in men with new mHSPC, and may assist with risk stratification of these patients for systemic therapy selection.

Predictive genomic markers of response to VEGF targeted therapy in metastatic renal cell carcinoma.

BACKGROUND: First-line treatment for metastatic renal cell carcinoma (mRCC) is rapidly changing. It currently includes VEGF targeted therapies (TT), multi-target tyrosine kinase inhibitors (TKIs), mTOR inhibitors, and immunotherapy. To optimize outcomes for individual patients, genomic markers of response to therapy are needed. Here, we aim to identify tumor-based genomic markers of response to VEGF TT to optimize treatment selection. METHODS: From an institutional database, primary tumor tissue was obtained from 79 patients with clear cell mRCC, and targeted sequencing was performed. Clinical outcomes were obtained retrospectively. Progression-free survival (PFS) on first-line VEGF TT was correlated to genomic alterations (GAs) using Kaplan-Meier methodology and Cox proportional hazard models. A composite model of significant GAs predicting PFS in the first-line setting was developed. RESULTS: Absence of VHL mutation was associated with inferior PFS on first-line VEGF TT. A trend for inferior PFS was observed with GAs in TP53 and FLT1 C/C variant. A composite model of these 3 GAs was associated with inferior PFS in a dose-dependent manner. CONCLUSION: In mRCC, a composite model of TP53 mutation, wild type VHL, and FLT1 C/C variant strongly predicted PFS on first-line VEGF TT in a dose-dependent manner. These findings require external validation.

Germline Variant in SLCO2B1 and Response to Abiraterone Acetate Plus Prednisone (AA) in New-onset Metastatic Castration-resistant Prostate Cancer (mCRPC).

There are many treatment options available for men with metastatic castration-resistant prostate cancer (mCRPC). Yet, biomarkers predictive of differential response to treatment are currently unavailable. A recent translational study suggested that SLCO2B1 genotype could predict response to abiraterone acetate for men with advanced prostate cancer. Here, we investigate whether germline variants in SLCO2B1 are predictive of response to first-line abiraterone acetate in men with new mCRPC. Clinical data and samples were analyzed from a prospective prostate cancer registry at the University of Utah (Salt Lake City, UT). Genotyping was performed using the Illumina OmniExpress genotyping platform. Primary endpoint was progression-free survival (PFS) on first-line abiraterone acetate in men with mCRPC. We performed a prespecified multivariate Cox regression analysis to assess the independent predictive value of rs12422149 and rs1789693 on PFS on abiraterone acetate. Of 401 men with advanced prostate cancer genotyped, 323 were homozygous wild-type for rs12422149 (80.5%), 74 were heterozygous (18.5%), and 4 were homozygous variant (1.0%). In a multivariate analysis of 79 men treated with first-line abiraterone acetate for mCRPC, men heterozygous for rs12422149 had significantly improved median PFS compared with the homozygous wild-type group (8.9 months vs. 6.3 months; HR, 0.46; 95% confidence interval, 0.23-0.94; P = 0.03). No significant difference in median PFS was seen by rs1789693 genotype. In this first clinical validation of translational data reported by Mostaghel and colleagues, germline variant alleles in rs12422149 of SLCO2B1 are common and predict improved response to first-line abiraterone acetate in men with mCRPC.

Germline Variant in HSD3B1 (1245 A > C) and Response to Abiraterone Acetate Plus Prednisone in Men With New-Onset Metastatic Castration-Resistant Prostate Cancer.

BACKGROUND: The HSD3B1 gene encodes the enzyme 3ß-hydroxysteroid dehydrogenase-1 (3ßHSD1), which catalyzes adrenal androgen precursors into dihydrotestosterone, the most potent androgen. Recently, the HSD3B1 (1245C) variant was shown to predict shorter duration of response to androgen deprivation therapy with medical or surgical castration in the setting of castration-sensitive prostate cancer (CSPC). The HSD3B1 (1245C) variant also predicts longer duration of response to ketoconazole in men with castration-resistant prostate cancer (CRPC). We hypothesized that the HSD3B1 (1245C) variant predicts response to treatment with abiraterone acetate (AA) and can help personalize treatment in men with advanced prostate cancer. METHODS: Clinical data and samples were from a prospectively maintained prostate cancer registry at the University of Utah. Genotyping was performed. The primary study end point was progression-free survival in first-line AA in men with metastatic CRPC. We performed prespecified multivariate analyses to assess the independent predictive value of HSD3B1 genotype on progression-free survival on AA. RESULTS: Seventy-six men with metastatic CRPC treated with first-line AA were included. In multivariate analysis, the HSD3B1 (1245C) variant did not predict response to first-line AA. CONCLUSION: The HSD3B1 (1245C) variant does not predict response to first-line AA in metastatic CRPC. This finding could be due to the ability of AA metabolites to act as both agonist (3-keto-5α-abiraterone) and antagonist (Δ4-abiraterone) on androgen signaling.

Overview of Current and Future First-Line Systemic Therapy for Metastatic Clear Cell Renal Cell Carcinoma.

OPINION STATEMENT: Treatment of metastatic clear cell renal cancer (mccRCC) has seen substantial progress over the last 20 years, with many regulatory approvals since 2006 culminating in a substantial increase to overall survival (OS). Six therapies are currently available for first-line use, with additional treatments currently being tested in this setting, some of which are expected to be approved soon based on new data from the CABOSUN and CheckMate-214 trials. Based on the available evidence, we strongly believe that vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI) therapy over mechanistic target or rapamycin (mTOR; formerly known as mammalian target of rapamycin) inhibitor therapy is the most effective first-line option regardless of risk category assignment. High-dose interleukin-2 (HDIL-2) therapy remains a reasonable treatment option in patients with Eastern Cooperative Oncology Group (ECOG) performance status 0-1 and have minimal comorbid conditions. In the near future, these agents are likely to be surpassed by cabozantinib and by combination immune checkpoint inhibitor therapy with nivolumab and ipilimumab. Independent review has recently confirmed superiority of first-line cabozantinib over sunitinib in a phase 2 trial of 157 patients with intermediate or poor risk mccRCC (progression-free survival [PFS] 8.6 vs 5.3 months, hazard ratio [HR] 0.48, p = 0.0008). In a separate study of 1096 patients treated with either upfront sunitinib or the combination of nivolumab and ipilimumab, those with intermediate and poor risk had significant improvement in both PFS (11.6 vs 8.4 months, HR 0.82, p = 0.0331) and OS (not reached vs 26 months, p < 0.0001). Responses were greater in patients with positive programmed death receptor ligand-1 (PD-L1) tumor staining, and pending regulatory approval may become standard of care in untreated patients with intermediate to poor risk disease with positive PD-L1 status. This likely represents the beginning of additional novel immunotherapy combinations for the first-line treatment of mccRCC.

Cancer immunotherapy: A paradigm shift in the treatment of advanced urologic cancers.

The recent resurgence of immunotherapy has transformed the therapeutic field of advanced urologic cancers. In this seminars issue, we evaluate the role of emerging and recently approved immunotherapeutic agents in advanced prostate, urothelial, and renal cell carcinoma. In each of these fields, we discuss recent regulatory approvals as well as promising ongoing clinical trials. Finally, we discuss incidence and management of immune related adverse events specifically associated with PD-1/PD-L1 inhibitors.

PD-1 checkpoint inhibition: Toxicities and management.

PURPOSE: With the recent approval of 5 PD-1/PD-L1 inhibitors for a number of malignancies, PD-1 axis inhibition is drastically changing the treatment landscape of immunotherapy in cancer. As PD-1/PD-L1 are involved in peripheral immune tolerance, inhibition of this immune checkpoint has led to novel immune-related adverse events including colitis, hepatitis, pneumonitis, rash, and endocrinopathies among many others. MATERIALS AND METHODS: In this seminar, we will analyze the incidence of immune-related adverse events for nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab. Then, we will discuss the specific management of the most common immune-mediated adverse events including colitis, hepatitis, pneumonitis, rash, endocrinopathies, nephritis, and neurologic toxicities. RESULTS: Immune-related adverse events are frequently treated with immunosuppressive medication such as steroids and mycofenolate mofetil. CONCLUSIONS: There are specific immune-related adverse events which are frequently seen by the treating oncologist from checkpoint inhibitors. It is essential to understand the recommended treatment options to minimize toxicity and mortality from this important class of anti-neoplastic therapies.

The future of immune checkpoint cancer therapy after PD-1 and CTLA-4.

The adaptive immune system plays an important role in eradicating malignant cells. Co-stimulatory and co-inhibitory signals to T cells though immune checkpoint receptors are involved in tumorigenesis and metastasis. Exploitation of immune checkpoint inhibitors, PD-1 and CTLA-4, with monoclonal antibodies has created impressive clinical responses. Many other immune checkpoint co-inhibitors and co-stimulators exist, including the B7 superfamily and tumor necrosis factor receptors superfamily. Here, we will examine co-inhibitors and co-stimulators beyond PD-1 and CTLA-4 that are being investigated in active clinical trials. We will review the immunology and preclinical studies that support investigation of these targets. Finally, we will briefly discuss the potential for immunotherapy to be combined with other treatment modalities.

Evolving Treatment Paradigm in Metastatic Renal Cell Carcinoma.

The treatment paradigm for advanced and metastatic renal cell carcinoma (mRCC) has evolved rapidly since the arrival of targeted therapies and novel immunotherapies. mRCC was previously treated only with cytokines. However, discoveries of mutations affecting the von Hippel-Lindau tumor suppressor gene (leading to increased expression of VEGF and hypoxia inducible factor/HIF-1) and of deregulations in the phosphatidylinositol-3 kinase/AKT/mTOR pathway (resulting in tumor angiogenesis, cell proliferation, and tumor growth) have led to the development of numerous targeted therapies. The U.S. Food and Drug Administration (FDA) has thus approved a total of nine targeted therapies since 2005, including VEGF tyrosine kinase inhibitors (sunitinib, pazopanib, axitinib, sorafenib, and lenvatinib), a monoclonal antibody targeting VEGF (bevacizumab), mTOR inhibitors (temsirolimus and everolimus), and a multityrosine kinase inhibitor (cabozantinib). Furthermore, the development of immune checkpoint inhibitors has again shifted the mRCC therapeutic landscape with the FDA's approval of nivolumab. Herein, we discuss the unprecedented changes in the field of clear cell histology mRCC in both the first-line and salvage settings, and we also discuss future therapies and recommend a treatment paradigm on sequencing of these agents.

Correlation of genomic alterations assessed by next-generation sequencing (NGS) of tumor tissue DNA and circulating tumor DNA (ctDNA) in metastatic renal cell carcinoma (mRCC): potential clinical implications.

INTRODUCTION: Tumor tissue and circulating tumor DNA (ctDNA) next-generation sequencing (NGS) testing are frequently performed to detect genomic alterations (GAs) to help guide treatment in metastatic renal cell carcinoma (mRCC), especially after progression on standard systemic therapy. Our objective was to assess if GAs detected by ctDNA NGS are different from those detected by tumor tissue NGS, specifically in patients with mRCC, and if these platforms are interchangeable or complimentary. RESULTS: When controlling for genes tested by both platforms, the median mutation rate for ctDNA was similar to tissue (median 3.0 vs. 1.0, p = 0.14). However, the concordance rate between the two platforms was only 8.6%. When comparing GAs by molecular pathway, GAs in tumor tissue were more common for the DNA repair and epigenetic pathways. MATERIALS AND METHODS: Results of NGS testing from tumor tissue and ctDNA from 19 sequential mRCC patients were compared. GAs in each were statistically evaluated using the Wilcoxon signed-rank test. The Fischer's exact test was used to compare the incidence of mutations in selected molecular pathways. CONCLUSIONS: When controlling for genes tested by both platforms, similar number of GAs were detected by both tissue and ctDNA based NGS. However, there was discordance in the type of GAs detected suggesting that ctDNA NGS may be more reflective of dynamic tumor genomic heterogeneity. Hence, these two platforms may be considered complementary to each other, rather than interchangeable, for assessment of tumor GAs to guide selection of targeted clinical trial therapies.

Incidence of Immune-Related Adverse Events with Program Death Receptor-1- and Program Death Receptor-1 Ligand-Directed Therapies in Genitourinary Cancers.

Program death receptor-1 (PD-1) and program death receptor-1 ligand (PD-L1) inhibitors are increasingly being used in the clinic to treat a growing number of malignancies, including many genitourinary (GU) malignancies. These immune-based therapies have demonstrated a distinct toxicity profile compared to traditional chemotherapy and the targeted therapies directed at the vascular endothelial growth factor pathway or the mammalian target of rapamycin pathway. Autoimmune toxicity targeting the skin, gastrointestinal tract, or the endocrine organs are some of the more common adverse events (AEs) noted with these therapies. Here in, we report the results of a systematic review of the incidence of toxicities in GU cancers reported in the phase II or phase III clinical trials using single-agent PD-1 or PD-L1 inhibitors. Overall, the rate of serious (grades 3-4) AEs was noted in approximately 15% of patients. The AEs noted were similar between all the agents tested, highlighting the overall class effect of these therapies. The incidence in GU cancers is similar to those seen in other malignancies. Given the widespread and high volume real-world use of these agents, it is important for oncologists to be familiar with these side effects to minimize the risks for patients while undergoing therapy.

Neutrophil-lymphocyte ratio as a predictive biomarker for response to high dose interleukin-2 in patients with renal cell carcinoma.

BACKGROUND: Immunotherapy with high-dose interleukin-2 (HD-IL2) results in long-term survival in some metastatic renal cell carcinoma (mRCC) patients but has significant acute toxicities. Biomarkers predicting response to therapy are needed to better select patients most likely to benefit. NLR (absolute neutrophil count (ANC)/absolute lymphocyte count (ALC)) is a prognostic and predicative biomarker in various malignancies. The goal was to determine whether NLR can predict response to HD-IL2 in this setting. METHODS: Patients with clear cell mRCC treated with HD-IL2 were identified from an institutional database from 2003-2012. Baseline variables for the assessment of IMDC risk criteria, and neutrophil and lymphocyte count, were collected. Best response criteria were based on RECIST 1.0. Wilcoxon rank-sum test was used to evaluate the association of continuous baseline variables with disease control. NLR was stratified by ≤4 or >4. Progression free survival (PFS) and overall survival (OS) were estimated with the Kaplan-Meier method and Cox proportional hazard models assessed associations of NLR with survival. RESULTS: In 71 eligible patients, median NLR in those with an objective response (n = 14, 20%) was 2.3 vs 3.4 in those without (n = 57, 80%, p = 0.02). NLR ≤4 was associated with improved progression free and overall survival. After adjustment for IMDC risk criteria, NLR remained a significant predictor of OS (ANC/ALC ≤4 vs >4, HR 0.41, 95% CI 1.09-5.46, p = 0.03; ANC/ALC continuous variable per unit change in NLR, HR 1.08, 95% CI 1.01-1.14, p = 0.03). CONCLUSIONS: In this discovery set, NLR predicts overall survival in patients treated with HD-IL2 in mRCC, and may allow better patient selection in this setting. Data needs validation in an independent cohort.

Conditional survival of metastatic renal cell carcinoma patients treated with high-dose interleukin-2.

Conditional survival (CS) is a clinically useful prediction measure which adjusts a patient's prognosis based on their duration of survival since initiation of therapy. CS has been described in numerous malignancies, and recently described in patients with metastatic renal cell carcinoma (mRCC) who received vascular endothelial growth factor tyrosine kinase inhibitor (VEGFTKI) therapy. However, CS has been not reported in the context of mRCC treated with high-dose interleukin-2 therapy (HDIL-2). A total of 176 patients with histologically confirmed metastatic clear cell RCC (mccRCC) treated with HDIL-2 at the University of Utah Huntsman Cancer Institute from 1988-2012 were evaluated. Using the Heng/IMDC model, they were stratified by performance status and prognostic risk groups. Two-year CS was defined as the probability of surviving an additional two years from initiation of HDIL-2 to 18 months after the start of HDIL-2 at three-month intervals. The median overall survival (OS) was 19.9 months. Stratifying patients into favourable (n = 35; 20%), intermediate (n = 110; 63%), and poor (n = 31; 18%) prognostic groups resulted in median OS of 47.5 (HR 0.57, 95% CI 0.35-0.88, p = 0.0106 versus intermediate), 19.6 (HR 0.33, 95% CI 0.10-0.33, p < 0.0001 versus poor), and 8.8 (HR 5.34, 95% CI 3.00-9.62, p < 0.0001 versus favourable) months respectively. Two-year overall CS increased from 43% at therapy initiation to 100% at 18 months. These results have significant ramifications in prognostication. Furthermore, it is important when counseling patients with mccRCC who have completed treatment with HDIL-2 and are in active follow-up.

Everolimus Versus Temsirolimus in Metastatic Renal Cell Carcinoma After Progression With Previous Systemic Therapies.

BACKGROUND: Everolimus is an approved agent for use after disease progression with vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) in patients with metastatic renal cell carcinoma. With recently published trials showing efficacy of nivolumab and cabozantinib in the second-line therapy setting, the use of everolimus will likely move to the third- or fourth-line therapy setting. Temsirolimus has occasionally been used instead of everolimus for many reasons, including financial considerations, assurance of patient compliance given its intravenous administration, its toxicity profile, patient performance status, and patient or physician preference. However, efficacy of everolimus and temsirolimus in this setting have not been compared in a randomized trial. The results from retrospective studies have been inconsistent. MATERIALS AND METHODS: We identified patients treated with a first-line VEGFR-TKI for metastatic renal cell carcinoma and then treated with either everolimus or temsirolimus on progression from the databases of 2 large academic cancer centers. Progression-free survival (PFS) and overall survival (OS) were assessed from the initiation of second-line treatment using the Kaplan-Meier method. RESULTS: A total of 90 patients received either everolimus (n = 59; 66%) or temsirolimus (n = 31; 34%) after progression during first-line VEGFR-TKI therapy. The patient and disease characteristics were similar in both groups. The median PFS was not different, but OS was superior with everolimus compared with temsirolimus (24.2 months vs. 12.1 months; hazard ratio, 0.58; P = .047). CONCLUSION: Our results bolster existing guidelines supporting everolimus over temsirolimus as salvage therapy after previous systemic therapies.