Risks and management of hypertension in cancer patients undergoing targeted therapy: a review.

BACKGROUND: Rapid progress over the last decade has added numerous agents targeting specific cellular signaling pathways to the treatment armamentarium for advanced cancer. However, many of these agents can cause hypertension resulting in major adverse cardiovascular event. METHODS AND RESULTS: A systematic literature search was performed on the databases PubMed and Google Scholar for papers published in English until December 2020. This review summarizes the risk, mechanism, diagnosis, and management of hypertension in cancer patients undergoing targeted therapy. The risk and pathogenesis of hypertension vary widely with different classes of targeted agents. Currently there is a paucity of data investigating optimal management of hypertension with targeted therapy. A practical approach is discussed with a focus on the goal of blood pressure control as well as drug selection based on the mechanism of hypertension in the context of advanced cancer, treatment toxicity, comorbidity, and drug-drug interactions. This review also discusses many studies that have explored hypertension as a biomarker for cancer treatment efficacy and as a pharmacodynamic biomarker to titrate drug dose. CONCLUSIONS: The diversity of targeted agents has provided important insights into the pathogenesis of hypertension in cancer patients. The underlying mechanism may provide a guidance to the management of hypertension. Further studies are needed to investigate optimal treatment and hypertension as a biomarker for cancer treatment.

Ibrutinib-associated dermatologic toxicities: A systematic review and meta-analysis.

The scope of dermatologic adverse events to ibrutinib has not been systematically described. We sought to determine the incidence and severity of ibrutinib-associated dermatologic toxicities and provide management recommendations. We conducted a systematic literature search of clinical trials and cohorts investigating ibrutinib monotherapy for cancer or chronic graft-versus-host disease through June 2020. Thirty-two studies with 2258 patients were included. The incidence of all-grade toxicities included cutaneous bleeds (24.8%; 95%CI, 18.6-31.0%), mucocutaneous infections (4.9%; 95%CI, 2.9-7.0%), rash (10.8%; 95%CI. 6.1-15.5%), mucositis (6%; 95%CI, 3.6-8.5%), edema (15.9%; 95%CI, 11.1-20.6%), pruritus (4.0%; 95%CI, 0.0-7.9%), xerosis (9.2%; 95%CI, 5.5-13.0%), nail changes (17.8%; 95%CI, 4.1-31.5%), and hair changes (7.9%; 95%CI, 0.0-21.3%). The incidence of high-grade toxicities included mucocutaneous infection (1.3%; 95%CI, 0.5-2.2%), rash (0.1%; 95%CI, 0.0-0.2%), mucositis (0.1%; 95%CI, 0.0-0.3%), and edema (0.1%; 95%CI, 0.0-0.2%). It is imperative that clinicians familiarize themselves with ibrutinib-associated dermatologic toxicities to learn how to manage them, prevent discontinuation, and improve patient outcomes.

Fatal Adverse Events Associated with Pembrolizumab in Cancer Patients: A Meta-Analysis.

Background: Pembrolizumab as an immune checkpoint inhibitor (ICI) has emerged as an effective treatment for many cancers. It has unique immune-related adverse events (irAE) and little is known about its risk of fatal adverse events (FAEs). We conducted a meta-analysis of clinical trials to determine the incidence and risk of FAEs with pembrolizumab.Methods: A systematic search for phase I-III clinical trials of pembrolizumab was conducted using databases including PUBMED and abstracts presented at the American Society of Clinical Oncology (ASCO) conferences until October 2018. Eligible studies included prospective clinical trials of pembrolizumab with available data on FAE. Data on FAE was extracted from each study and pooled for calculations. Incidence, relative risk (RR) and 95% confidence intervals (CI) were calculated by employing fixed or random-effects models.Results: A total of 11 clinical trials with 3713 patients were included for analysis. The overall incidence of FAE with pembrolizumab was 1.2% (95% CI: 0.5-2.8%). The incidence of FAE significantly varied among different tumor types (p = .02), ranging from 0.2% in melanoma to 3.1% in breast cancer, and with its combination with chemotherapy (0.7%, 95% CI: 0.4-1.2% versus 7.0%, 95% CI: 4.9-10%; p<.01). Chemotherapy plus pembrolizumab 7.0% (95%CI: 4.9-10) as compared to pembrolizumab alone 0.7%, (95% CI: 0.4-1.2; p < .001). There was no significant difference in the risk of FAEs when pembrolizumab was compared with chemotherapy with RR = 1.24 (95% CI: 0.8-1.89; p = .31). The most common FAEs were due to infectious complication (26.5%), cardiac toxicity (14.7%) and pneumonitis (13.2%).Conclusions: The risk of FAEs with pembrolizumab may be similar to chemotherapy in cancer patients and may vary with tumor types and its combination with chemotherapy.

Emerging therapeutic agents for genitourinary cancers.

The treatment of genitourinary malignancies has dramatically evolved over recent years. Renal cell carcinoma, urothelial carcinoma of the bladder, and prostate adenocarcinoma are the most commonly encountered genitourinary malignancies and represent a heterogeneous population of cancers, in both histology and approach to treatment. However, all three cancers have undergone paradigm shifts in their respective therapeutic landscapes due to a greater understanding of their underlying molecular mechanisms and oncogenic drivers. The advance that has gained the most recent traction has been the advent of immunotherapies, particularly immune checkpoint inhibitors. Immunotherapy has increased overall survival and even provided durable responses in the metastatic setting in some patients. The early success of immune checkpoint inhibitors has led to further drug development with the emergence of novel agents which modulate the immune system within the tumor microenvironment. Notwithstanding immunotherapy, investigators are also developing novel agents tailored to a variety of targets including small-molecule tyrosine kinase inhibitors, mTOR inhibitors, and novel fusion proteins to name a few. Erdafitinib has become the first targeted therapy approved for metastatic bladder cancer. Moreover, the combination therapy of immune checkpoint inhibitors with targeted agents such as pembrolizumab or avelumab with axitinib has demonstrated both safety and efficacy and just received FDA approval for their use. We are in an era of rapid progression in drug development with multiple exciting trials and ongoing pre-clinical studies. We highlight many of the promising new emerging therapies that will likely continue to improve outcomes in patients with genitourinary malignancies.

Increased Risk of Hypertension with Enzalutamide in Prostate Cancer: A Meta-Analysis.

Hypertension is associated with enzalutamide in the treatment of prostate cancer. We performed a meta-analysis of randomized clinical trials to determine the risk of hypertension. Databases including Pubmed and Google scholar were searched to identify randomized clinical trials with enzalutamide. A total of seven studies including 7347 patients were selected. The overall incidences of all-grade and high-grade hypertension were 11.9% (95%% CI: 8.8-16.0%) and 4.9% (95%% CI: 3.5-6.8%) respectively, with a relative risk of 2.82 (95%% CI: 2.34-3.38, p < 0.001) for all-grade and 2.27 (95%% CI: 1.73-2.96, p < 0.001) for high-grade. There was a significant risk of developing hypertension with enzalutamide.

Risk of hypertension in cancer patients treated with abiraterone: a meta-analysis.

BACKGROUND: Hypertension is one of the major side effects associated with abiraterone in the treatment of advanced prostate cancer. The specific contribution of abiraterone to hypertension has not been defined. We performed a systematic review and meta-analysis of randomized clinical trials to determine its overall risk. METHODS: Databases including Pubmed (up to July 2018) and Google scholar (up to July 2018) were searched to identify relevant studies. Eligible studies were prospective randomized clinical trials with prostate cancer treated with abiraterone and prednisone. The incidence and relative risk (RR) of hypertension was calculated using random-effects or fixed-effects model depending on the heterogeneity of included studies. RESULTS: A total of five studies including 5445 patients were selected for analysis. Among patients receiving abiraterone, the overall incidences of all grade and high grade (grade 3 and 4) were 21.9% (95% CI: 13.6-33.2%) and 10.2% % (95% CI: 6.9-11.6%). Abiraterone was associated with a significantly increased risk of hypertension of all grade with a relative risk of 1.80 (95% CI: 1.47-2.19%, p < 0.001) and high grade with a relative risk of 2.11 (95%CI: 1.66-2.68%, p < 0.001) in comparison with controls. The risk of hypertension may be affected by concurrent use of prednisone with 5 mg daily is associated with higher incidence than that of prednisone 5 mg twice daily (32.4% vs 16.5%). CONCLUSION: There is a significant increase of developing hypertension in prostate cancer patients treated with abiraterone. Appropriate monitoring and management is strongly recommended to reduce the risk of cardiovascular events and treatment interruptions.

Risk of hypertension in Cancer patients treated with Abiraterone: a meta-analysis.

BACKGROUND: Hypertension is one of the major side effects associated with abiraterone in the treatment of advanced prostate cancer. The specific contribution of abiraterone to hypertension has not been defined. We performed a systematic review and meta-analysis of randomized clinical trials to determine its overall risk. METHODS: Databases including Pubmed (up to July 2018) and Google scholar (up to July 2018) were searched to identify relevant studies. Eligible studies were prospective randomized clinical trials with prostate cancer treated with abiraterone and prednisone. The incidence and relative risk (RR) of hypertension was calculated using random-effects or fixed-effects model depending on the heterogeneity of included studies. RESULTS: A total of five studies including 5445 patients were selected for analysis. Among patients receiving abiraterone, the overall incidences of all grade and high grade (grade 3 and 4) were 21.9% (95% CI: 13.6-33.2%) and 10.2% % (95% CI: 6.9-11.6%). Abiraterone was associated with a significantly increased risk of hypertension of all grade with a relative risk of 1.80 (95% CI: 1.47-2.19%, p < 0.001) and high grade with a relative risk of 2.11 (95%CI: 1.66-2.68%, p < 0.001) in comparison with controls. The risk of hypertension may be affected by concurrent use of prednisone with 5 mg daily is associated with higher incidence than that of prednisone 5 mg twice daily (32.4% vs 16.5%). CONCLUSION: There is a significant increase of developing hypertension in prostate cancer patients treated with abiraterone. Appropriate monitoring and management is strongly recommended to reduce the risk of cardiovascular events and treatment interruptions.

An evaluation of nivolumab for the treatment of metastatic renal cell carcinoma.

INTRODUCTION: The treatment paradigm for metastatic renal cell carcinoma (mRCC) has undergone a revolution with the rapid market approval of multiple agents over a three-year period. The immunogenicity of renal cell carcinoma (RCC) provided the biological rationale to assess the clinical efficacy of nivolumab, an immune checkpoint inhibitor. Nivolumab is approved for second-line treatment after failure of angiogenesis-targeted therapy and in combination therapy with ipilimumab for previously untreated intermediate- or poor-risk advanced RCC. Areas covered: The authors review the preclinical and clinical data supporting nivolumab employment in mRCC. Discussion of the underlying mechanisms of immunotherapy, data on objective responses, safety and tolerability, regulatory affairs, and future directions of nivolumab therapy are highlighted. Expert opinion: Nivolumab serves as a proof-of-principle of the efficacy of immunotherapy with checkpoint inhibition in mRCC. Nivolumab may be considered the leading monotherapy in the second-line setting for patients with low tumor volume considering its risks and benefits. Nivolumab was recently approved in the first-line setting as part of combination therapy with another immune modulator. Moreover, nivolumab use may offer clinicians the option for treatment beyond progression as emerging data has indicated possible overall survival benefits in this setting. Ongoing clinical studies may result in nivolumab use in the first-line setting, as monotherapy or in combination therapy with antiangiogenesis agents.

Current and Emerging Therapeutic Targets for Metastatic Renal Cell Carcinoma.

PURPOSE OF REVIEW: The treatment of advanced renal cell carcinoma has evolved dramatically over recent years. In this review, we will summarize current and emerging therapies based on molecular targets and provide insight into treatment strategy for metastatic renal cell carcinoma. RECENT FINDINGS: We have witnessed a paradigm shift in the therapeutic landscape as treatment was formerly reliant on cytokine-based agents which have now been replaced with therapies targeting angiogenesis, mammalian target of rapamycin pathways, and immune responses. These dramatic changes are primarily due to our improved understanding of the underlying mutations and molecular mechanisms leading to tumorigenesis and progression. We now have targeted agents in the form of small-molecule tyrosine kinase inhibitors, monoclonal antibodies, and mTOR inhibitors. Moreover, immunotherapy-targeting checkpoints of T-lymphocyte activity has provided increased overall survival and a new class of agents with potential to radically change the treatment options. With these agents and their combination, durable responses are increasingly seen even though treatment resistance remains a huge challenge. New treatment strategies are rapidly developing and the therapeutic landscape is expected for further evolution.

Risk of Liver Toxicity with Nivolumab Immunotherapy in Cancer Patients.

BACKGROUND: Nivolumab is approved for the treatment of many cancers. This meta-analysis was conducted to determine the risk of hepatotoxicity with nivolumab therapy. METHODS: An analysis from all phase I-III clinical trials up to December 2016 examining nivolumab was conducted. Data on elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were extracted from the safety profiles of each trial. Incidence and relative risk (RR) were calculated using random- or fixed-effects models with 95% confidence intervals (CIs). RESULTS: The incidences of all-grade and high-grade elevations in AST were 5.4% (95% CI 3.2-9.1) and 1.6% (95% CI 0.9-3.0), respectively. The incidences of all-grade and high-grade elevations in ALT were 4.9% (95% CI 2.9-8.2) and 1.7% (95% CI 0.9-3.1), respectively. Elevations of both laboratory markers were significantly increased when compared to control (p < 0.001). Nivolumab significantly increased the RR of AST/ALT elevations; RRs were 1.58 (95% CI 1.1-2.2) for all-grade AST elevation, and 1.62 (95% CI 1.2-2.3) for all-grade ALT elevation. Subgroup analysis of all-grade AST or ALT elevation revealed a signi-ficant variation among tumor types (p < 0.001) and with combination with ipilimumab (p < 0.001). CONCLUSIONS: Nivolumab is associated with significantly increased risk of liver toxicity.

Pigmentary changes in patients treated with targeted anticancer agents: A systematic review and meta-analysis.

BACKGROUND: The discovery of signaling networks that drive oncogenic processes has led to the development of targeted anticancer agents. The burden of pigmentary adverse events from these drugs is unknown. OBJECTIVE: To conduct a systematic review and meta-analysis of published clinical trials and determine the incidence and risk of development of targeted therapy-induced pigmentary changes. METHODS: A comprehensive search was conducted to identify studies reporting targeted therapy-induced pigmentary changes. The incidence and relative risk were calculated. Case reports and series were reviewed to understand clinical characteristics. RESULTS: A total of 8052 patients from 36 clinical trials were included. The calculated overall incidences of targeted cancer therapy-induced all-grade pigmentary changes in the skin and hair were 17.7% (95% confidence interval [CI], 11.9-25.4) and 21.5% (95% CI, 14.9-30.1), respectively. The relative risk of all-grade pigmentary changes of skin and hair were 93.7 (95% CI, 5.86-1497.164) and 20.1 (95% CI, 8.35-48.248). Across 53 case reports/series (N = 75 patients), epidermal growth factor receptor and breakpoint cluster region-abelson inhibitors were the most common offending agents. LIMITATIONS: Potential under-reporting and variability in oncologists reporting these events. CONCLUSION: There is a significant risk of development of pigmentary changes during treatment with targeted anticancer therapies. Appropriate counseling and management are critical to minimize psychosocial impairment and deterioration in quality of life.

Discontinuation of Everolimus Due to Related and Unrelated Adverse Events in Cancer Patients: A Meta-Analysis.

A meta-analysis of randomized controlled trials (RCTs) was performed to examine the risk of everolimus discontinuation due to related and unrelated adverse events (AE) in cancer patients. Fifteen RCTs were analyzed that compared everolimus to placebo and reported discontinuation due to AE with everolimus (related and unrelated to everolimus) and placebo (unrelated to everolimus). Incidence of discontinuation with everolimus due to AE and placebo was 12.3% and 4.7% respectively. Relative risk of everolimus discontinuation due to related AE was 2.60. Risk of discontinuation varied by tumor type, however everolimus dose or concomitant chemotherapy was not significant.

New treatment options for metastatic renal cell carcinoma with prior anti-angiogenesis therapy.

Angiogenesis is a critical process in the progression of advanced renal cell carcinoma. Agents targeting angiogenesis have played a primary role in the treatment of metastatic renal cell carcinoma. However, resistance to anti-angiogenesis therapy almost always occurs, and major progress has been made in understanding its underlying molecular mechanism. Axitinib and everolimus have been used extensively in patients whom have had disease progression after prior anti-angiogenesis therapy. Recently, several new agents have been shown to improve overall survival in comparison with everolimus. This review provides an in-depth summary of drugs employable in the clinical setting, the rationale to their use, and the studies conducted leading to their approval for use and provides perspective on the paradigm shift in the treatment of renal cell carcinoma. Highlighted are the newly approved agents cabozantinib, nivolumab, and lenvatinib for advanced renal cell carcinoma patients treated with prior anti-angiogenesis therapy.

Attributable Risk of Infection to mTOR Inhibitors Everolimus and Temsirolimus in the Treatment of Cancer.

The risk of infection attributable to mTOR inhibitors has not been determined. Databases from PubMed and abstracts presented at the American Society of Clinical Oncology meetings were searched. Eligible studies included randomized controlled trials, in which everolimus or temsirolimus was compared with placebo. A total of 12 trials were included. The attributable incidences of all-grade and high-grade infections to mTOR inhibitors were 9.3% (95% confidence interval (CI): 5.8-14.6%) and 2.3% (95% CI: 1.2-4.4%) respectively. The risk varied widely with tumor types (p <.001). There was substantial risk of infection attributable to mTOR inhibitors everolimus and temsirolimus.

Risk of hyperglycemia attributable to everolimus in cancer patients: A meta-analysis.

Everolimus has been used widely in cancer patients and is associated with the development of hyperglycemia. Due to confounding factors, its specific impact on hyperglycemia has not been well understood. We performed a meta-analysis of randomized controlled trials to determine the risk of hyperglycemia attributable to everolimus in cancer patients of varying tumor types. MATERIAL AND METHODS: PubMed and American Society of Clinical Oncology conference abstracts up to June 2015 were systematically searched. Eligible studies included randomized controlled trials (RCTs) in which everolimus was compared to placebo in cancer patients with or without other agents. Heterogeneity tests were performed to examine between-study differences in hyperglycemia, and the incidence and relative risk of all- and high-grade hyperglycemia attributable to everolimus were determined using both random- or fixed-effects models. RESULTS: A total of seven phase III and two phase II RCTs with various tumors, encompassing a total of 3879 cancer patients, were included in our analysis. Everolimus significantly increased the risk of all-grade (RR =2.60, 95% CI 2.03-3.31, p < 0.001) and high-grade (RR =3.0, 95% CI 1.72-5.23; p < 0.001) hyperglycemia. The incidences of all- and high-grade hyperglycemia attributable to everolimus were 6.8% (95% CI 3.4-13.2%) and 2.5% (95% CI 1.2-4.9%), respectively. The everolimus-specific risk of all-grade hyperglycemia varied significantly with tumor types (p < 0.001), with the highest incidence seen in renal cell carcinoma (RCC) (27.2%, 95% CI 22.2-32.8%) and the lowest in breast cancer (3.3%, 95% CI 1.3-8.2%). No significant variation was found between everolimus alone or everolimus in combination with other agents. Similar results were also found for the risk of high-grade hyperglycemia attributable to everolimus. CONCLUSION: The specific risk of hyperglycemia attributable to everolimus may vary significantly with tumor types. Close monitoring should be given to patients at high risk, such as RCC.

Novel therapy for advanced gastric cancer.

Gastric cancer (GC) is a common lethal malignancy. Gastroesophageal junction and gastric cardia tumors are the fastest rising malignancies due to increasing prevalence of obesity and acid reflex in the United States. Traditional chemotherapy remains the main treatment with trastuzumab targeting human epidermal growth factor receptor 2 positive disease. The median overall survival (OS) is less than one year for advanced GC patients; thus, there is an urgent unmet need to develop novel therapy for GC. Although multiple targeted agents were studied, only the vascular endothelial growth factor receptor inhibitor ramucirumab was approved recently by the United States Food and Drug Administration because of its 1.4 mo OS benefit (5.2 mo vs 3.8 mo, P = 0.047) as a single agent; 2.2 mo improvement of survival (9.6 mo vs 7.4 mo, P = 0.017) when combined with paclitaxel in previously treated advanced GC patients. It is the first single agent approved for previously treated GC and the second biologic agent after trastuzumab. Even with limited success, targeted therapy may be improved by developing new biomarkers. Immune therapy is changing the paradigm of cancer treatment and is presently under active investigation for GC in clinical trials. More evidence supports GC stem cells existence and early stage studies are looking for its potential therapeutic possibilities.

Comparative analysis of the effectiveness of abiraterone before and after docetaxel in patients with metastatic castration-resistant prostate cancer.

AIM: To study the efficacy and safety of abiraterone in patients with and without prior chemotherapy. METHODS: The databases including PubMed and abstracts presented at the American Society of Clinical Oncology meetings up to April 2014 were systematically searched. Eligible studies included randomized controlled trials (RCTs) in which abiraterone plus prednisone was compared to placebo plus prednisone in metastatic castration-resistant prostate cancer (CRPC) patients. The summary incidence, relative risk, hazard ratio and 95%CI were calculated using random or fixed-effects models. Heterogeneity test was performed to test between-study differences in efficacy and toxicity. RESULTS: A total of two phase III RCTs were included in our analysis, with metastatic CPRC patients before (n = 1088) and after chemotherapy (n = 1195). Prior chemotherapy did not significantly alter the effect of abiraterone on overall survival (P = 0.92) and prostate-specific antigen (PSA) progression-free survival (P = 0.13), but reduced its effect on radiographic-progression-free survival (P = 0.04), objective response rate (P < 0.001), and PSA response rate (P < 0.001). Prior chemotherapy significantly increased the specific risk of fluid retention and edema (P < 0.001) and hypokalemia (P < 0.001), but decreased the risk of all-grade hypertension (P < 0.001) attributable to abiraterone. There was no significant difference of cardiac disorders associated with abiraterone between the two settings (P = 0.58). CONCLUSION: Prior chemotherapy may reduce the effectiveness of abiraterone in patients with metastatic CRPC.