Jeanny B. Aragon-Ching

American Cancer Society prostate cancer survivorship care guidelines.

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VEGF Inhibitors and Prostate Cancer Therapy

Prostate cancer remains the most common non-cutaneous malignancy among American men. Since the advent of PSA testing, most men are diagnosed with localized disease, but a proportion of men will be diagnosed with metastatic disease, many will eventually receive chemotherapy with docetaxel and prednisone. However, responses are not durable and all men will ultimately progress on this treatment. As such, continued efforts are geared towards the discovery of new agents and mechanisms of targeting prostate cancer. Angiogenesis has been shown to play an important role in tumorigenesis, proliferation and metastasis in prostate cancer. Here we discuss the major angiogenic signaling pathway involving VEGF in prostate cancer progression and the role of various promising agents that targets this pathway. This includes bevacizumab, thalidomide and its analogues, tyrosine kinase inhibitors sorafenib and AZD2171, and other inhibitors of angiogenic signaling pathways. Results of key clinical trials associated with the use of these agents and future directions are discussed herein.

Docetaxel As Monotherapy or Combined With Ramucirumab or Icrucumab in Second-Line Treatment for Locally Advanced or Metastatic Urothelial Carcinoma: An Open-Label, Three-Arm, Randomized Controlled Phase II Trial

PURPOSEnThis trial assessed the efficacy and safety of docetaxel monotherapy or docetaxel in combination with ramucirumab (vascular endothelial growth factor receptor 2 antibody) or icrucumab (vascular endothelial growth factor receptor 1 antibody) after progression during or within 12 months of platinum-based regimens for patients with locally advanced or metastatic urothelial carcinoma.nnnPATIENTS AND METHODSnPatients were randomly assigned (1:1:1) to receive docetaxel 75 mg/m(2) intravenously (IV) on day 1 of a 3-week cycle (arm A), docetaxel 75 mg/m(2) IV plus ramucirumab 10 mg/kg IV on day 1 of a 3-week cycle (arm B), or docetaxel 75 mg/m(2) IV on day 1 plus icrucumab 12 mg/kg IV on days 1 and 8 of a 3-week cycle (arm C). Treatment continued until disease progression or unacceptable toxicity. The primary end point was investigator-assessed progression-free survival (PFS).nnnRESULTSnA total of 140 patients were randomly assigned and treated in arms A (n = 45), B (n = 46), or C (n = 49). PFS was significantly longer in arm B compared with arm A (median, 5.4 months; 95% CI, 3.1 to 6.9 months v 2.8 months; 95% CI, 1.9 to 3.6 months; stratified hazard ratio, 0.389; 95% CI, 0.235 to 0.643; P = .0002). Arm C did not experience improved PFS compared with arm A (1.6 months; 95% CI, 1.4 to 2.9; stratified hazard ratio, 0.863; 95% CI, 0.550 to 1.357; P = .5053). The most common grade 3 or worse adverse events (arms A, B, and C) were neutropenia (36%, 33%, and 39%), fatigue (13%, 30%, and 20%), febrile neutropenia (13%, 17%, and 6.1%), and anemia (6.7%, 13%, and 14%, respectively).nnnCONCLUSIONnThe addition of ramucirumab to docetaxel met the prespecified efficacy end point for prolonging PFS in patients with locally advanced or metastatic urothelial carcinoma receiving second-line treatment and warrants further investigation in the phase III setting.

Angiogenesis Inhibition in Prostate Cancer: Current Uses and Future Promises

Angiogenesis has been well recognized as a fundamental part of a multistep process in the evolution of cancer progression, invasion, and metastasis. Strategies for inhibiting angiogenesis have been one of the most robust fields of cancer investigation, focusing on the vascular endothelial growth factor (VEGF) family and its receptors. There are numerous regulatory drug approvals to date for the use of these agents in treating a variety of solid tumors. While therapeutic efficacy has been established, challenges remain with regards to overcoming resistance and assessing response to antiangiogenic therapies. Prostate cancer is the most common noncutaneous malignancy among American men and angiogenesis plays a role in disease progression. The use of antiangiogenesis agents in prostate cancer has been promising and is hereby explored.

Mechanisms of drug resistance to vascular endothelial growth factor (VEGF) inhibitors.

Angiogenesis inhibitors have a major role in the treatment of varying cancers today. While originally thought to be independent of resistance, increasing data suggests varying mechanisms that bring about drug resistance, either intrinsically or through adaptation. The role of vascular endothelial growth factor single nucleotide polymorphisms (VEGF SNPs) in terms of therapeutic response and toxicity has increasingly been recognized, as well as its potential for contributing to drug resistance. This review will focus on theories, preclinical models, and clinical trials that help elucidate the mechanisms of resistance and clinical response to angiogenesis inhibitors.

Hematuria in sickle cell trait: the importance of ruling out occult cancer

Dear Editor, Sickle cell trait is characterized by a heterozygous inheritance of the sickle hemoglobin gene. Unlike sickle cell disease, sickle cell trait is commonly viewed as a benign process in asymptomatic patients [1]. However, a growing number of case reports and observational studies reveal that complications do occur in these individuals [2]. Both microscopic and gross hematuria are the most common complication [3]. About 50% of these cases have been attributed to renal papillary necrosis [4]. Despite this association, the diagnostic workup for cases of hematuria should always include a urine analysis, urine culture, urine cytology, computed tomography (CT) with and without contrast, and cystoscopy with ureteroscopy if necessary. This report aims to highlight the importance of careful diagnostic workup in patients with sickle cell trait presenting with hematuria. A 49-year-old African–American male with sickle cell trait presented with a history of intermittent, sharp left flank pain, and gross hematuria throughout micturition. Aside from hematuria, all other studies including a noncontrast abdomen/pelvis CT scan were unremarkable. His condition was initially attributed to a kidney stone due to spontaneous resolution. However, these episodes recurred with passage of dark red tissue 3 weeks later. A repeat CT was ordered, this time with contrast, along with cystoscopy. Both studies were again negative despite persistence of his symptoms. Given his long history of sickle cell trait and a negative workup, his hematuria was attributed to papillary necrosis. However, his flank pain progressively worsened with continued passage of necrotic tissue, unrelieved by hydration and urine alkalization. He was referred to the hematology clinic where repeat studies were obtained given the severity and increased frequency of his symptoms. An abdomen/pelvis CT revealed a filling defect in the upper collecting system of the left kidney (Fig. 1), suspicious for malignancy, along with multiple subcentimeter periaortic lymph nodes. A retrograde pyelogram confirmed these findings. Ureteroscopy and biopsy demonstrated a high-grade, non-invasive papillary urothelial carcinoma involving the renal pelvis, extending into the left proximal ureter. A metastatic workup including cystoscopy was unremarkable aside from previously noted lymphadenopathy. Laparoscopic left nephroureterectomy was performed with no further evidence of cancer. Two months later, multiple bladder lesions, biopsy-proven as “drop metastases”, were found on cystoscopy and treated with fulguration. He was treated with intravesical mitomycin C and a 6-week course of Bacille Calmette-Guerin (BCG). Since that time, his adenopathy has been stable and he has had only one recurrence at the bladder dome that was treated with fulguration. Intravesical BCG will be continued for another 6 weeks with frequent monitoring for recurrence. B. S. Gill (*) School of Medicine, The George Washington University, 922 24th Street NW, Apt 421, Washington, DC 20037, USA e-mail: bsgill@gwmail.gwu.edu

Cytotoxic Compounds in the Treatment of Castration-Resistant Prostate Cancer

Prostate cancer is the most common non-cutaneous cancer among men in the United States. Most will be diagnosed at an early stage, but a significant number will still develop metastatic castration resistant disease. Docetaxel has demonstrated improved quality of life and overall survival in metastatic castration-resistant prostate cancer but virtually all patients will ultimately become refractory to taxane therapy. Second-line options are limited and new effective chemotherapeutic agents or combinations are needed in this setting. This review will focus on cytotoxic compounds in clinical investigation either in combination with taxanes in the first or second-line setting and other novel compounds, such as platinums and microtubule-targeting agents that are in active clinical investigation.

Investigational Angiogenesis Inhibitors

Targeting angiogenesis is an evolving field of cancer research. Tumor angiogenesis is considered as an important step in the progression and metastasis of prostate cancer. Several pathways that converge toward promotion of growth, proliferation, and survival of prostate cancer cells have been targeted, including modulation of proangiogenic factors such as vascular endothelial growth factor (VEGF), tyrosine kinases, cytokines, and the extracellular matrix. Accurately measuring antitumor activity remains a challenge with the use of investigational angiogenesis inhibitors in prostate cancer.

Targeting the androgen receptor in metastatic castration-resistant prostate cancer

*Department of Medicine, Division of Hematology & Oncology, George Washington University Medical Center, 2150 Pennsylvania Avenue, NW, Washington, DC 20037, USA; Tel.: +1 202 741 2478; Fax: +1 202 741 2487; jaragonching@mfa.gwu.edu Androgen deprivation therapy (ADT) has been the cornerstone of treatment for metastatic prostate cancer. Since the emergence of castration resistance, attempts to define mechanisms of resistance has led the field into a search for non-androgen receptor (AR)-driven targets. This brought on an era of investigation that began with the use of chemotherapy for prostate cancer. While chemotherapy has been one of the earliest established treatments for men with symptomatic prostate cancer, based on the TAX327 and SWOG 9916 trials, it has only recently been established that the role of chemotherapy may not be limited to microtubule inhibition alone, but also inhibition of AR nuclear translocation [1,2]. The perception that the AR ceases to become a therapeutic target also heralded a generation of agents targeting alternative nonandrogen-dependent pathways that showed promising results in Phase II trials, but failed to provide survival benefit when tested in larger prospective Phase III trials. The landscape of treatment was truly revolutionized when further AR manipulation via the use of androgen biosynthesis inhibitors and novel antiandrogens came into fruition. The traditional concept of testicular androgen suppression was considered insufficient when increased intraprostatic and intratumoral androgens were considered contributors to further testosterone production, which brought about the concept of CYP17 enzyme inhibition that would later give rise to the development and approval of abiraterone acetate in 2011 and 2012 for both postchemotherapy metastatic castration-resistant prostate cancer (CRPC) patients [3], as well as prechemotherapy-naive patients [4], respectively. Similarly, peripheral androgen blockade with novel second-generation enzalutamide provided a unique profile as it was selected from a library of compounds for its AR inhibition of cells overexpressing the AR, which is far more potent than bicalutamide and was approved in 2012 for postchemotherapy metastatic CRPC patients. In addition, the more recently concluded PREVAIL trial has been reported [5] and enzalutamide has been shown to statistically improve overall survival in men who were chemotherapy-naive compared with patients receiving placebo (p < 0.0001). Enzalutamide provided a 30% reduction in risk of death compared with placebo (hazard ratio: 0.70; 95% CI: 0.59–0.83). Jeanny B Aragon-Ching* “The discovery of novel androgen biosynthesis inhibitors and second-generation antiandrogens are only the beginning of a host of agents that can circumvent the androgen receptor machinery.”

Bevacizumab and Angiogenesis Inhibitors in the Treatment of CNS Metastases: The Road less Travelled

The incidence of central nervous system (CNS) metastases secondary to solid tumors is increasing. As more effective systemic therapy is being used in patients with solid tumors, patients with cancer live longer and are ultimately at higher risk for CNS metastases. However, CNS metastases remain challenging to treat because of limited available therapeutic options. This article reviews mechanisms of CNS metastases, the use of bevacizumab and other angiogenesis inhibitors in the treatment of recurrent and front-line CNS metastases, as well as emerging issues of resistance to anti-angiogenic therapy.