Revisiting Treatment of Metastatic Urothelial Cancer: Where Do Cisplatin and Platinum Ineligibility Criteria Stand?

Cisplatin-based chemotherapy has been the standard of care in metastatic urothelial cancer (mUC) for more than two decades. However, many patients with comorbidities cannot receive cisplatin or its alternative, carboplatin. 'Cisplatin-ineligible' and 'platinum-ineligible' patients lacked effective therapy options. However, the recent combination of enfortumab vedotin (EV), an antibody-drug conjugate targeting Nectin-4, with pembrolizumab (P), an antibody targeting the programmed death-1 (PD-1) immune checkpoint, is changing the status quo of frontline mUC treatment, with potential synergy seen in the EV-103 and EV-302 clinical trials. First, we review the working definitions of 'cisplatin ineligibility' and 'platinum ineligibility' in mUC clinical trials and the standard of care in both categories. Then, we review select clinical trials for frontline treatment of cisplatin- and platinum-ineligible mUC patients on ClinicalTrials.gov. We classify the investigated drugs in these trials by their therapeutic strategies. Alongside chemotherapy combinations, the field is witnessing more immunotherapy combinations with fibroblast growth factor receptor (FGFR) inhibitors, bicycle toxin conjugates, bispecific antibodies, innovative targeted therapies, and many others. Most importantly, we rethink the value of classifying patients by cisplatin or platinum ineligibility in the frontline setting in the post-EVP era. Lastly, we discuss new priority goals to tailor predictive, monitoring, and prognostic biomarkers to these emergent therapies.

Durable Objective Response to Lurbinectedin in Small Cell Bladder Cancer with TP53 Mutation: A Molecular-Directed Strategy.

Small cell bladder cancer (SCBC) is a rare and aggressive disease, often treated with platinum/etoposide-based chemotherapy. Key molecular drivers include the inactivation of onco-suppressor genes (TP53, RB1) and amplifications in proto-oncogenes (MYC). We report a patient with SCBC who achieved an objective and prolonged response to lurbinectedin, which has been approved for metastatic small cell lung cancer, after developing disease progression on cisplatin/etoposide and nivolumab/ipilimumab. A genomic analysis of a metastatic biopsy prior to lurbinectedin initiation revealed a TP53 mutation and amplification of the cell cycle regulators E2F3 and MYCL. A repeat biopsy following the development of lurbinectedin resistance showed a new actionable ERBB2 alteration without significant change in the tumor mutation burden (six mutations/Mb). The present report suggests that lurbinectedin may be active and should be further explored in SCBC harboring TP53 mutations and amplifications in E2F3 and MYC family complexes.

Brain Metastasis in the Emergency Department: Epidemiology, Presentation, Investigations, and Management.

Brain metastases (BMs) are the most prevalent type of cerebral tumor, significantly affecting survival. In adults, lung cancer, breast cancer, and melanoma are the primary cancers associated with BMs. Symptoms often result from brain compression, and patients may present to the emergency department (ED) with life-threatening conditions. The goal of treatment of BMs is to maximize survival and quality of life by choosing the least toxic therapy. Surgical resection followed by cavity radiation or definitive stereotactic radiosurgery remains the standard approach, depending on the patient's condition. Conversely, whole brain radiation therapy is becoming more limited to cases with multiple inoperable BMs and is less frequently used for postoperative control. BMs often signal advanced systemic disease, and patients usually present to the ED with poorly controlled symptoms, justifying hospitalization. Over half of patients with BMs in the ED are admitted, making effective ED-based management a challenge. This article reviews the epidemiology, clinical manifestations, and current treatment options of patients with BMs. Additionally, it provides an overview of ED management and highlights the challenges faced in this setting. An improved understanding of the reasons for potentially avoidable hospitalizations in cancer patients with BMs is needed and could help emergency physicians distinguish patients who can be safely discharged from those who require observation or hospitalization.

Antiangiogenic Tyrosine Kinase Inhibitors have Differential Efficacy in Clear Cell Renal Cell Carcinoma in Bone.

Clear cell renal cell carcinoma (ccRCC) is the most prevalent kidney neoplasm; bone metastasis (BM) develops in 35% to 40% of metastatic patients and results in substantial morbidity and mortality, as well as medical costs. A key feature of ccRCC is the loss of function of the von Hippel-Lindau protein, which enhances angiogenesis via vascular endothelial growth factor release. Consequently, antiangiogenic tyrosine kinase inhibitors (TKI) emerged as a treatment for ccRCC. However, limited data about their efficacy in BM is available, and no systematic comparisons have been performed. We developed mouse models of bone and lung ccRCC tumors and compared their anticancer efficacy, impact on mouse survival, and mechanisms of action, including effects on tumor cells and both immune and nonimmune (blood vessels and osteoclasts) bone stromal components. This approach elucidates the efficacy of TKIs in ccRCC bone tumors to support rational interrogation and development of therapies. SIGNIFICANCE: TKIs showed different efficacy in synchronous bone and lung metastases and did not eradicate tumors as single agents but induced extensive reprogramming of the BM microenvironment. This resulted in a significant decrease in neoangiogenic blood vessels, bone remodeling, and immune cell infiltration (including CD8 T cells) with altered spatial distribution.

An overview of hormonal directed pharmacotherapy for the treatment of prostate cancer.

INTRODUCTION: Prostate cancer is the most common malignancy in the male. Androgen-deprivation therapy (ADT) has been the mainstay in the treatment of metastatic prostate cancer however, due to the outgrowth of castration-resistant cell population the disease inevitably progresses to an aggressive, difficult to handle stage. AREAS COVERED: We have reviewed the literature regarding hormonal-directed therapy prostate cancer. New agents, namely abiraterone acetate, combined with prednisone, and next generation antiandrogens (enzalutamide, apalutamide and darolutamide) have shown considerable efficacy, not only in patients with metastatic but also in those with non-metastatic disease, either castration resistant (CRPC) or hormone sensitive (HSPC). EXPERT OPINION: The addition of abiraterone and of the second-generation antiandrogens to our therapeutic armamentarium has improved prognosis ofprostate cancer in the last decade. Abiraterone is a viable option in patients with metastatic disease (hormone-sensitive and castration-resistant), whereas all next-generation antiandrogens have demonstrated efficacy in terms of metastasis-free and overall survival in non-metastatic CRPC. In addition, enzalutamide has also been found efficacious in mCRPC and mHSPC, while apalutamide in mHSPC. Currently there are no reliable data to indicate a potential superiority of one of these agents over the others in CRPC or HSPC as there are no relevant head to head studies . Sequencing hormone treatment modalities, chemotherapies and immunotherapies have not reached a consensus as yet. Randomized controlled trials are warranted to clearly define the role of novel antiandrogens in the treatment of prostate cancer. The choice of treatment should be individualized following discussion with the patient .

Recurrent miscarriage and male factor infertility: diagnostic and therapeutic implications. A narrative review.

Introduction: Recurrent miscarriage is defined as 2 or more failed clinical pregnancies, typically known as repeated pregnancy loss, occurring before 20 gestational weeks, and further categorized into primary and secondary types. It represents a common and distressing condition to deal with in the field of reproductive medicine, usually affecting <5% of couples, with up to 50% of cases lacking a clearly defined aetiology. The epidemiology also varies depending on maternal age. Remarkably, the situation significantly afflicts expecting parents, whereas maternal factors, such as age and previous pregnancy loss rate, are commonly reported as risk factors. Although previously underestimated, existing evidence suggests the male factor is a possible cause of recurrent pregnancy loss. Material and methods: A non-systematic literature review was conducted in the PubMed and Scopus databases for articles written in English investigating the possible association of the male factor in recurrent pregnancy loss. The eligible studies were synthesized in a narrative review format upon discussion and consensus among the authors after being previously independently assessed and selected. Results: Lifestyle, obesity, genetic predisposition, chromosomal anomalies, endocrine dysfunction, anatomical abnormalities, immunological factors, infections, and oxidative stress can result in poor embryo development and recurrent miscarriage. Although professional organizations currently recognize male gender as a possible risk factor, specific recommendations on the diagnostic and therapeutic field are still lacking, and the condition necessitates a high level of suspicion and case-by-case management. Conclusions: In this review, we delve deeper into the contribution of the male factor in the concept of recurrent miscarriage.

Comparative Effectiveness Analysis of Treatment Strategies for Surgically Resectable Neuroendocrine Carcinoma of the Urinary Tract.

BACKGROUND: Neoadjuvant chemotherapy (neoCTX) has been recommended as the optimal strategy in surgically resectable neuroendocrine carcinoma (NEC) of the urinary tract (NEC-URO). OBJECTIVE: To determine the systemic therapy regimen and timing, which are most active against NEC-URO. DESIGN, SETTING, AND PARTICIPANTS: We used our institutional historical clinical and pathological database to study 203 patients (cT2, 74%; cT3/4a, 22%; and cTx, 4%) with surgically resectable NEC-URO between November 1985 and May 2020. A total of 141 patients received neoCTX and 62 underwent initial radical surgery, 24 of whom received adjuvant CTX (adjCTX). INTERVENTION: Neoadjuvant CTX with etoposide/cisplatin (EP), an alternating doublet of ifosfamide/doxorubicin (IA) and EP, dose-dense methotrexate/vinblastine/doxorubicin/cisplatin (MVAC), gemcitabine/cisplatin (GC), or others. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Overall survival (OS), downstaging rate, and pathological complete response using a multivariable model adjusting for tumor- and patient-related factors. RESULTS AND LIMITATIONS: Downstaging rate was significantly improved with neoCTX versus initial surgery (49.6% vs 14.5%, p < 0.0001), stage cT2N0 versus cT3/4N0 (44% vs 25%, p = 0.01), or presence of carcinoma in situ (47% vs 28%, p = 0.01). Downstaging was greatest with IA/EP (65%) versus EP (39%), MVAC/GC (27%), or others (36%, p = 0.04). After adjusting for age and Eastern Cooperative Oncology Group performance status, IA/EP was still associated with improved downstaging (odds ratio = 3.7 [1.3-10.2], p = 0.01). At a median follow-up of 59.7 mo, 5-yr OS rates for neoCTX followed by surgery, surgery alone, and surgery followed by adjCTX were 57%, 22%, and 30%, respectively. An NEC regimen (IA/EP or EP) versus a urothelial regimen (MVAC/GC or others) was associated with improved survival (145.4 vs 42.5 mo, hazard ratio = 0.49, 95% confidence interval: 0.25-0.94). CONCLUSIONS: Neoadjuvant CTX remains the standard-of-care treatment for NEC-URO with an advantage for NEC regimens over traditional urothelial regimens. IA/EP improves pathological downstaging at the time of surgery compared with EP, but is reserved for younger and higher function patients. PATIENT SUMMARY: In this report, we looked at the outcomes from invasive neuroendocrine carcinoma of the urinary tract in a large US population. We found that the outcomes varied with treatment strategy. We conclude that the best outcomes are seen in patients treated with chemotherapy prior to surgery and regimens tailored to histology and tolerance.

Prostate cancer immunotherapy.

INTRODUCTION: Medical treatment for prostate cancer (PC) targets hormonal pathways used by malignant cells. Research advances aided in gaining knowledge about implicated molecular pathways and opened the way for establishment of new types of therapies by modifying immunological mechanisms. The aim of this review is to present completed and ongoing research projects regarding PC immunotherapy. AREAS COVERED: A literature search was conducted in PubMed/MEDLINE, Scopus, Cochrane Central Register of Controlled Trials, and https://www.clinicaltrials.gov/ from inception until 07/2021, to identify completed or ongoing Phase III trials regarding several immunotherapies against PC. Studies on vaccine therapies, CTLA-4 inhibitors, PD-1/PD-L1 inhibitors, PARP inhibitors, PSMA-targeted therapies, and tyrosine kinase inhibitors were considered eligible. EXPERT OPINION: Although many molecules are being tested against PC cells, only sipuleucel-T has gain approval in the USA. The main reason for this delay in establishing immunotherapy as a standard option for managing PC is the heterogeneity and tumor immune microenvironment complexities. Ipilimumab and olaparib were proved to prolong overall survival significantly against placebo, but a lot of research is going on to identify which patients and at what stage of disease will benefit the most before incorporating them in clinical practice. More recent options such as PSMA-targeted treatments are currently evaluated. ARTICLE HIGHLIGHTS: Intense research performed on immunotherapy for prostate cancer.Vaccine therapy with sipuleucel-T, the only approved immunotherapy for prostate cancer.Ipilimumab shows survival benefits.Olaparib shows survival benefits.Findings should be confirmed on further trials to identify target population characteristics and proper disease stage.Immunotherapy is not yet a standard due to tumor environment complex interaction between immune system and malignant cells.