The incidence of major bleeding in adult patients with urogenital and gynecological cancer being treated with direct oral anticoagulants (DOACs): a systematic review.

BACKGROUND: Direct oral anticoagulants (DOACs) are the mainstay of treatment for venous thromboembolism (VTE) and non-valvular atrial fibrillation (AF), with or without an underlying cancer. Patients with cancer have a 2-3-fold increase in risk for bleeding complications compared to non-cancer patients taking anticoagulant therapy, however the incidence of bleeding for urogenital and gynecological cancers on DOACs are uncertain. AIMS: To assess the bleeding risk associated with the use of DOACs in patients with urogenital and/or gynecological cancers. METHOD: We conducted a systematic review of randomized controlled trials (RCTs) and prospective cohort studies to address the safety of DOACs for VTE and AF when used in patients with urogenital and/or gynecological malignancy. The primary outcomes assessed were major and clinically relevant non-major (CRNMB) bleeding, with minor bleeding considered as a secondary outcome. MEDLINE, EMBASE and COCHRANE Central Registry of Controlled Trials were searched up to and including Oct 28, 2022. The study protocol was registered in PROSPERO (CRD42022370981). Studies were independently assessed for inclusion and data extracted in duplicate. RESULT: Seven studies met our inclusion criteria (Fig. 1): 2 RCTs and 5 prospective cohort studies. A total of 676 patients treated with DOACs were included, 628 (92.8%) had VTE and 48 (7.1%) had AF. In patients with VTE treated with DOACs, the pooled major bleeding rate was 2.1%, 95% confidence intervals (CI) 0.9-3.3% (Fig. 2). Pooled estimates could not be determined for AF patients given small event and patient numbers. CONCLUSION: Major bleeding rates in urogenital and/or gynecological cancer patients treated with DOACs are similar to that of the general cancer population.

Results of a multicenter, phase 2 study of nivolumab and ipilimumab for patients with advanced rare genitourinary malignancies.

BACKGROUND: In this multicenter, single-arm, multicohort, phase 2 trial, the efficacy of nivolumab and ipilimumab was evaluated in patients with advanced rare genitourinary cancers, including bladder and upper tract carcinoma of variant histology (BUTCVH), adrenal tumors, platinum-refractory germ cell tumors, penile carcinoma, and prostate cancer of variant histology (NCT03333616). METHODS: Patients with rare genitourinary malignancies and no prior immune checkpoint inhibitor exposure were enrolled. Patients received nivolumab at 3 mg/kg and ipilimumab at 1 mg/kg intravenously every 3 weeks for 4 doses, and this was followed by 480 mg of nivolumab intravenously every 4 weeks. The primary endpoint was the objective response rate (ORR) by the Response Evaluation Criteria in Solid Tumors (version 1.1). RESULTS: Fifty-five patients were enrolled at 6 institutions between April 2018 and July 2019 in 3 cohorts: BUTCVH (n = 19), adrenal tumors (n = 18), and other tumors (n = 18). The median follow-up was 9.9 months (range, 1 to 21 months). Twenty-eight patients (51%) received 4 doses of nivolumab and ipilimumab; 25 patients received nivolumab maintenance for a median of 4 cycles (range, 1-18 cycles). The ORR for the entire study was 16% (80% confidence interval, 10%-25%); the ORR in the BUTCVH cohort, including 2 complete responses, was 37%, and it was 6% in the other 2 cohorts. Twenty-two patients (40%) developed treatment-related grade 3 or higher toxicities; 24% (n = 13) required high-dose steroids (≥40 mg of prednisone or the equivalent). Grade 5 events occurred in 3 patients; 1 death was treatment related. CONCLUSIONS: Nivolumab and ipilimumab resulted in objective responses in a subset of patients with rare genitourinary malignancies, especially those with BUTCVH. An additional cohort exploring their activity in genitourinary tumors with neuroendocrine differentiation is ongoing. LAY SUMMARY: Patients with rare cancers are often excluded from studies and have limited treatment options. Fifty-five patients with rare tumors of the genitourinary system were enrolled from multiple sites and were treated with nivolumab and ipilimumab, a regimen used for kidney cancer. The regimen showed activity in some patients, particularly those with bladder or upper tract cancers of unusual or variant histology; 37% of those patients responded to therapy. Additional studies are ongoing to better determine who benefits the most from this combination.

Ciprofloxacin and Levofloxacin as Potential Drugs in Genitourinary Cancer Treatment-The Effect of Dose-Response on 2D and 3D Cell Cultures.

INTRODUCTION: Introducing new drugs for clinical application is a very difficult, long, drawn-out, and costly process, which is why drug repositioning is increasingly gaining in importance. The aim of this study was to analyze the cytotoxic properties of ciprofloxacin and levofloxacin on bladder and prostate cell lines in vitro. METHODS: Bladder and prostate cancer cell lines together with their non-malignant counterparts were used in this study. In order to evaluate the cytotoxic effect of both drugs on tested cell lines, MTT assay, real-time cell growth analysis, apoptosis detection, cell cycle changes, molecular analysis, and 3D cultures were examined. RESULTS: Both fluoroquinolones exhibited a toxic effect on all of the tested cell lines. In the case of non-malignant cell lines, the cytotoxic effect was weaker, which was especially pronounced in the bladder cell line. A comparison of both fluoroquinolones showed the advantage of ciprofloxacin (lower doses of drug caused a stronger cytotoxic effect). Both fluoroquinolones led to an increase in late apoptotic cells and an inhibition of cell cycle mainly in the S phase. Molecular analysis showed changes in BAX, BCL2, TP53, and CDKN1 expression in tested cell lines following incubation with ciprofloxacin and levofloxacin. The downregulation of topoisomerase II genes (TOP2A and TOP2B) was noticed. Three-dimensional (3D) cell culture analysis confirmed the higher cytotoxic effect of tested fluoroquinolone against cancer cell lines. CONCLUSIONS: Our results suggest that both ciprofloxacin and levofloxacin may have great potential, especially in the supportive therapy of bladder cancer treatment. Taking into account the low costs of such therapy, fluoroquinolones seem to be ideal candidates for repositioning into bladder cancer therapeutics.

Integration of Patient Reported Outcomes in Drug Development in Genitourinary Cancers.

PURPOSE OF REVIEW: Patient reported outcomes (PROs) are increasingly utilized in cancer drug development, and are of particular importance in genitourinary cancers due to symptom burden, multiple treatment options with similar efficacy, and often prolonged duration of disease. Here we review current data and perspectives related to use of PROs in drug development for genitourinary cancers, including insights on the regulatory process for drug approval. RECENT FINDINGS: The FDA is committed to incorporating PRO data into the regulatory process for development and approval of new cancer drugs, but challenges exist due to lack of standardization of PRO instrument choice and analytic approach, missing data, and difficulty isolating treatment effect from disease-related effects. We review guidance for standardization of PRO methodology that is nonetheless tailored to disease state and anticipated effects of treatment. PRO and efficacy data should be simultaneously analyzed and reported for best clinical practice. Multiple disease-specific PRO instruments exist for genitourinary cancers. While clinicians, researchers, and regulatory bodies alike recognize the importance of PROs in cancer drug development, challenges remain regarding implementation of best practices.

Impact of a formal pharmacist-run oral antineoplastic monitoring program: A pilot study in an adult genitourinary oncology clinic.

BACKGROUND: In recent years, there has been a changing paradigm in the management of oncologic disease states from the use of intravenous therapies, requiring a visit to the infusion center or hospitalization, to new therapies that can be administered orally.1,2 Several publications have evaluated the role pharmacists may play in the initial prescribing of oral chemotherapy, however the impact of a formalized pharmacist follow-up program has not been well defined. This study evaluates the impact of a pilot pharmacist-run oral antineoplastic monitoring program. METHODS: This retrospective cohort analysis evaluated patients prescribed an oral antineoplastic in the genitourinary oncology clinic at an academic medical center between 1 July 2014 and 15 March 2017. Patients enrolled in the program were compared to a historical control group. The primary objective was adherence to pre-defined standards for monitoring. Secondary objectives include persistence on therapy, need to seek medical care, analysis of pharmacist interventions, patient satisfaction, and financial impact for the on-site retail pharmacy. RESULTS: In total, 33 patients were evaluated (11 cases, 22 controls). Average adherence to monitoring recommendations was significantly higher in the case group compared to controls (89% vs. 61%; p = 0.008). In total, 67 interventions were made by the clinical pharmacist with an average of 6 per patient. CONCLUSIONS: This study shows that formalized pharmacist follow-up programs can improve patients' adherence with antineoplastic monitoring standards. Additionally, pharmacists made clinically significant interventions and had high patient satisfaction, providing justification for expansion into other disease states.

Interstitial brachytherapy for pediatric soft tissue sarcoma: Evolving practice over three decades and long-term outcomes.

PURPOSE: Evaluate long-term clinical outcomes, adverse effects, and evolving practice of interstitial brachytherapy (BT) for pediatric soft tissue sarcomas (STS). METHODS: From September 1984 to December 2014, 105 children (median age 10 years) were included. There were 60 males and 45 females. The majority (74%) had primary lesions. Synovial sarcoma (22%) was the most frequent histology. Treatment included wide local excision and BT with or without external beam radiotherapy (EBRT). Eighty-five (81%) received BT alone. RESULTS: After a median follow-up of 65 months, local control (LC), disease-free survival (DFS), and overall survival (OS) at 10 years were 83, 66, and 73%, respectively. On univariate analysis, LC was superior with tumors <5 cm versus >5 cm (93% vs. 75%, P = 0.10), Grade I/II versus Grade III tumors (97% vs. 73%, P = 0.01), nonround cell versus round cell histology (89% vs. 72%, P = 0.03), and trunk/extremity versus head and neck/genitourinary sites (87% vs. 57%, P = 0.0001). On multivariate analysis tumor size (P = 0.03) and location (P = 0.002) retained significance. Children receiving BT alone had comparable LC to those receiving BT and EBRT (84% vs. 80%, P = 0.43). There was no difference in LC between LDR versus HDR BT (86% vs. 83%, P = 0.30). Wound complications were seen in 6%. Subcutaneous fibrosis (25%), limb edema (6%), skeletal abnormalities (3%), and neuropathy (1%) were the late complications. One child (0.9%) developed a second malignancy after 7 years. CONCLUSION: Interstitial BT with or without EBRT results in excellent outcomes. Radical BT alone, when used judiciously, results in excellent local control and function with minimal treatment-related morbidity.

Targeting the Tumor Microenvironment with Immunotherapy for Genitourinary Malignancies.

OPINION STATEMENT: Bacillus Calmette-Guérin in urothelial carcinoma, high-dose interleukin-2 in renal cell carcinoma, and sipuleucel-T in prostate cancer serve as enduring examples that the host immune response can be harnessed to promote effective anti-tumor immunity in genitourinary malignancies. Recently, cancer immunotherapy with immune checkpoint inhibitors has transformed the prognostic landscape leading to durable responses in a subset of urothelial carcinoma and renal cell carcinoma patients with traditionally poor prognosis. Despite this success, many patients fail to respond to immune checkpoint inhibitors and progression/relapse remains common. Furthermore, modest clinical activity has been observed with ICIs as a monotherapy in advanced PCa. As such, novel treatment approaches are warranted and improved biomarkers for patient selection and treatment response are desperately needed. Future efforts should focus on exploring synergistic and rational combinations that safely and effectively boost response rates and survival in genitourinary malignancies. Specific areas of interest include (1) evaluating the optimal sequencing, disease burden, and timing of immuno-oncology agents with other anti-cancer therapeutics and (2) validating novel biomarkers of response to immunotherapy to optimize patient selection and to identify individuals most likely to benefit from immunotherapy across the heterogenous spectrum of genitourinary malignancies.

Endocrine, Sexual Function, and Infertility Side Effects of Immune Checkpoint Inhibitor Therapy for Genitourinary Cancers.

PURPOSE OF REVIEW: Immune checkpoint therapy has grown in prominence in the last few decades and is being increasingly utilized in treatment of advanced cancers. Although information on toxicities of these drugs is forthcoming, not much is known regarding the toxicity profile of these drugs from a sexual function standpoint. We undertook the current review to appraise the literature for endocrine/sexual side effects of anti-PD-1/PD-L1 and anti-CTLA-4 therapy. RECENT FINDINGS: Our review included 32 articles and focused primarily on the programmed death (PD) pathway. We found that endocrine side effects after anti-PD-1/PD-L1 therapy are relatively rare, with hypothyroidism (range < 1 to 40%) and hypophysitis (range < 1 to 10%) being the two most common. None of the studies specifically commented on the infertility or sexual side effects of these drugs. However, two studies evaluating biochemical profiles of patients undergoing therapy with ipilimumab (a CTLA-4 inhibitor) or combination therapy (CTLA-4 + PD-1/PD-L1 inhibitors) noted that about < 1 to ~ 60% of the patients developed hypogonadotropic hypogonadism. None of the studies provided information regarding clinically meaningful sexual health endpoints such as libido, erectile function assessments, or sexual function-related quality of life. Endocrine side effects, although uncommon, are important and unique side effects of immune checkpoint therapy because they are often complex and can be life threatening. While side effects on sexual health may not be life threatening, they are lifestyle limiting. Thus, long-term follow-up, post-marketing surveillance, and future studies will need to elucidate the true rates of endocrine/sexual side effects and the mechanisms underlying them. This will aid in better counseling of the patients, as more of them undergo these novel immune checkpoint inhibitor therapies.

Chance of reimbursement for ADD-ON therapies in Poland and in the world - review of the reimbursement recommendations

INTRODUCTION: Oncology drugs combined with standard therapies (so-called add-on therapies, e.g. bevacizumab, palbociclib) often receive negative recommendations regarding the legitimacy of public financing, issued by government agencies responsible for their assessment, i.e. health technology assessment agencies. The aim of the study was to estimate the scale of the problem related to the reimbursement of add-on therapies used in the treatment of breast and genitourinary cancers in Poland and in the world. MATERIAL AND METHODS: A multimodal approach was used to select add-on therapies. The reimbursement routes were analysed in 8 reference countries (Poland, Canada, England, Wales, France, Scotland, Australia, New Zealand). Based on a systematic search, data for breast and urogenital cancers were included. RESULTS: A total of 68 reimbursement documents for add-on therapies were identified. The analysis showed that in Poland, 20% of innovative schemes including add-on therapies should be reimbursed, while in the world the percentage of positive recommendations reaches 56%. It was observed that globally (including data for Poland) the chance for a favorable reimbursement recommendation for add-on therapies is 53%, with 29% being positive recommendations with limitations. In Poland, the majority of negative recommendations concern genitourinary cancers in comparison to breast cancer (83% vs 75%). CONCLUSIONS: Poland is at the head of the countries in terms of the number of negative reimbursement recommendations. Bearing in mind the world's need of modifying the criteria for the evaluation of oncological therapies in the context of the possibility of their reimbursement, one should expect a change in the approach to the assessment of the legitimacy of financing innovative add-on therapies in Poland.

Rare neoplasm of genito-urinary tract. Genito-urinary sarcomas: chemotherapy.

PURPOSE OF REVIEW: The purpose of this article was to describe the systemic therapy of genito-urinary sarcomas. RECENT FINDINGS: High rate of distant metastasis and high mortality rate has brought interest into the development of new therapeutic approaches. Various modules of chemotherapy were sampled in sarcoma treatment, although clinical response is still unsatisfactory. Chemotherapy in sarcomas can be used as neoadjuvant or adjuvant to the surgery. There is no consensus on the current role of adjuvant chemotherapy. Study results are conflicting; therefore, conclusions drawn from the studies are uncertain. In general, the adjuvant chemotherapy is not standard treatment in adult-type sarcomas. In addition, chemotherapy for advanced and metastatic sarcoma disease, as well as second-line chemotherapy, was discussed. SUMMARY: The best treatment for sarcomas in case of organ-confined disease and in selected cases of locally advanced disease seems to be surgery followed by chemotherapy. In case of metastasis stage of sarcoma, preoperative chemotherapy with surgery of residual masses should be considered as first-line treatment followed by postoperative chemotherapy. The treatment of patient with highly advanced disease and/or unresectable metastases should be individualized (chemotherapy, radiotherapy and best supportive care).

Cabozantinib in genitourinary malignancies.

Cabozantinib inhibits a variety of cellular receptors including VEGFR1-3, MET, AXL, RET, FLT3 and KIT. These signaling pathways have been shown to be important in genitourinary malignancies. Along its clinical development, it has shown most activity in advanced renal cell carcinoma; the METEOR study compared cabozantinib to everolimus and showed clinically and statistically significant improvements in both progression-free survival and overall survival. Herein, we review the development of cabozantinib in the genitourinary malignancies of renal cell carcinoma, prostate adenocarcinoma and urothelial carcinoma.

The Effect of Targeted Therapy for Genitourinary Malignancies on Sexual Function and Fertility.

PURPOSE OF REVIEW: Targeted therapy for genitourinary cancer is being used at an increasing rate. These medications show great survival benefit but are relatively lacking in long-term adverse effect data. With increasing survivability, measures to improve quality of life must be considered for GU cancer and a large proponent of this is sexual function. RECENT FINDINGS: mTOR inhibitors have shown an effect on testosterone levels and may have a link to abnormal semen parameters. Tyrosine kinase inhibitors (TKIs) have shown no adverse sexual outcomes in the literature. There are laboratory links to tyrosine kinases having a beneficial effect on erectile and sexual function. Possible sexual side effects must be discussed with patients receiving a diagnosis of cancer. Further research is required to determine the exact mechanisms and outcomes of sexual function with new and emerging targeted therapy.

Role of protein phosphatases in genitourinary cancers.

The prevalence of genitourinary cancers has been increasing rapidly worldwide over the past 10 years. Advances in diagnosis and treatment have improved the oncological outcomes of patients with genitourinary cancer. However, the precise mechanisms of cancer development are largely unknown. Among various biological mechanisms, reversible phosphorylation is crucial for regulating the activities of many proteins in cancer cells. In contrast to protein kinases, the roles of cellular protein phosphatases have not been fully elucidated. However, emerging evidence suggests that various protein phosphatases are involved in genitourinary cancer development and have potential for cancer treatment. In the present review, we focus on recent progress in protein phosphatases regarding genitourinary cancers. We also explore the development of new strategies for cancer therapy using protein phosphatase and related molecules.

[Immunotherapy in uropathology]. / Immunothérapie en uropathologie.

The algorithms for treatment of metastatic cancers are evolving due to positive results obtained with immunotherapy. Therapeutics approaches to stimulate the immune system have already been used in the treatment of kidney and bladder cancer, such as the administration of cytokines and BCG therapy, confirming the immunogenicity of these tumors. The aim of immunotherapies is not only to activate the immune system against tumor cells, but also to take into account the tumor-induced suppressive microenvironment, in particular by removing the anergy of T-cell lymphocytes, and by targeting the co-stimulation inhibitors molecules. Among the genito-urinary cancers, second-line clinical trials have clearly shown that kidney and bladder cancers are sensitive to the inhibition of PD-1/PD-L1 axis and have already achieved FDA approvals for some molecules. Numerous other clinical trials are underway, particularly in first-line treatment in bladder and renal cancers. Refractory testicular cancer could also benefit from these treatments. Other approaches using vaccine therapy especially in castration-resistant prostate cancer are also of interest. We will see, in this chapter dedicated to the urogenital cancers, the benefit of the immunotherapy by resituating it in the genetic and immunological context of each organ. We will also present briefly the therapeutic outlines and the place of biomarkers.

Genitourinary tumours in the targeted therapies era: new advances in clinical practice and future perspectives.

Genitourinary cancers represent a heterogeneous group of malignancies arising from genitourinary tract, and are responsible for almost 359 000 newly diagnosed cases and 58 420 related deaths in USA. Continuous advances in cancer genetics and genomics have contributed towards changing the management paradigms of these neoplasms. Neoangiogenesis, through the activation of the tyrosine-kinase receptors signalling pathways, represents the key mediator event in promoting tumour proliferation, differentiation, invasiveness and motility. In the last decade, several treatments have been developed with the specific aim of targeting different cell pathways that have been recognized to drive tumour progression. The following review attempts to provide a comprehensive overview of the literature, focusing on new advances in targeted therapies for genitourinary tumours. Furthermore, the promising results of the latest clinical trials and future perspectives will be discussed.

Programmed cell death-1 pathway inhibitors in genitourinary malignancies: specific side-effects and their management.

PURPOSE OF REVIEW: Immune checkpoint inhibitors such as those that target the programmed cell death (PD)-1 pathway harness the host immune system to elicit an antitumor response. Their remarkable clinical benefit has led to regulatory approvals in several malignancies including the genitourinary cancers, renal cell carcinoma, and urothelial carcinoma. This review will focus on the management of the toxicities encountered with these agents. RECENT FINDINGS: Although generally well tolerated, a small proportion of patients (10-20%) treated with PD-1 directed agents as monotherapy can develop severe autoimmune manifestations, also known as, immune-related adverse events. These include but are not limited to rashes, pneumonitis, endocrinopathy, colitis, and immune-mediated hepatic dysfunction. Combining these agents with the anti-CTLA-4 antibody ipilimumab can be associated with a higher incidence of these toxicities. Early initiation of immunosuppression with corticosteroids and other agents when needed can help mitigate these toxicities and to date has not been shown to compromise their clinical benefit. SUMMARY: The development of immune checkpoint inhibitors represents significant advances in anticancer therapy but their efficacy may come at the cost of autoimmune toxicities secondary to their induction of the immune system. Early recognition of these effects and aggressive upfront management is essential to safely administer these agents in routine clinical practice.

Physician-pharmacist collaboration for oral chemotherapy monitoring: Insights from an academic genitourinary oncology practice.

BACKGROUND: Oral chemotherapy is being routinely used in metastatic castrate-resistant prostate and renal cell cancer. Although convenient, these drugs require monitoring for adherence, toxicity, and drug interactions to maximize outcomes. Oncology pharmacists have the training and expertise that place them in an optimal position to collaboratively provide medication therapy management. METHODS: A board-certified oncology pharmacist, working in collaboration with a medical oncologist, initiated an oral chemotherapy-monitoring program. The pharmacist provided education, completed medication therapy management; monitored for adherence and toxicity; and recommended treatment of toxicity and supportive care issues. Patient encounters included one of the following: collaboration with medical oncologist visit, pharmacist visit, or telephone or email follow-up between visits. RESULTS: From December 2012 to May 2014, the pharmacist had 123 encounters with 20 patients with either metastatic prostate (n = 17) or renal cell cancer (n = 3). All patients were males (median age 80 years). Most encounters were clinic visits, in collaboration with physician visit or alone (52%); 36% were telephone encounters, and 11.3% were email follow-ups. Medication-related problems were identified in 25% of the 315 assessments made. Problems included: adverse drug reactions, 40%; inappropriate therapy, 20%; and noncompliance, 18%. Recommendations included: modification of laboratory monitoring, 25%; cancer or non-cancer therapy modification, 12%; drug discontinuation, 6.9%. Non-cancer therapy-related drug information and coordination of care accounted for 30% of recommendations. CONCLUSION: Our program led to identification of a number of potentially clinically significant issues for patients on oral chemotherapy and demonstrated the benefit of the pharmacist in the multidisciplinary team to assist in addressing them.

Resistance exercise training in patients with genitourinary cancers to mitigate treatment-related skeletal muscle loss.

The use of targeted therapies in patients with genitourinary malignancies has significantly improved outcomes. For example, androgen receptor (AR) pathway inhibitors have improved outcomes for patients with prostate cancer, and antiangiogenic agents have improved outcomes for those with kidney cancer. However, these advances have been accompanied by musculoskeletal side effects that manifest as physical dysfunction. Although the effects of androgen deprivation therapy on skeletal muscle are well-known, an additional concern is that the muscle loss associated with these newer drugs-especially AR pathway inhibitors-may result in insulin resistance and metabolic syndrome, thus increasing the risk for cardiovascular events and diabetes. Antiangiogenic agents also may cause muscle loss, although this has been poorly described in the literature. As these targeted therapies begin to be used in the earlier stages of treatment, there will be a critical need to prevent treatment-related toxicities with nonpharmacologic interventions. Over the past decade, exercise training has emerged as a novel nonpharmacologic adjunctive method to address toxicities resulting from these targeted therapies. Despite numerous studies in patients with prostate cancer, there remains a large gap in our knowledge of the true efficacy of exercise therapy, as well as the best way to prescribe exercise programs. Here, we suggest that the central role of skeletal muscle in the development of side effects of AR pathway inhibitors and antiangiogenic agents may unlock a number of unique opportunities to study how exercise prescriptions can be used more effectively. Resistance training may be a particularly important modality.