The Impact of Positron Emission Tomography Imaging and Tumor Molecular Profiling on Risk Stratification, Treatment Choice, and Oncological Outcomes of Patients with Primary or Relapsed Prostate Cancer: An International Collaborative Review of the Existing Literature.

CONTEXT: The clinical introduction of next-generation imaging methods and molecular biomarkers ("radiogenomics") has revolutionized the field of prostate cancer (PCa). While the clinical validity of these tests has thoroughly been vetted, their clinical utility remains a matter of investigation. OBJECTIVE: To systematically review the evidence to date on the impact of positron emission tomography (PET) imaging and tissue-based prognostic biomarkers, including Decipher, Prolaris, and Oncotype Dx, on the risk stratification, treatment choice, and oncological outcomes of men with newly diagnosed PCa or those with biochemical failure (BCF). EVIDENCE ACQUISITION: We performed a quantitative systematic review of the literature using the MEDLINE, EMBASE, and Web of Science databases (2010-2022) following the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement guidelines. The validated Quality Assessment of Diagnostic Accuracy Studies 2 scoring system was used to assess the risk of bias. EVIDENCE SYNTHESIS: A total of 148 studies (130 on PET and 18 on biomarkers) were included. In the primary PCa setting, prostate-specific membrane antigen (PSMA) PET imaging was not useful in improving T staging, moderately useful in improving N staging, but consistently useful in improving M staging in patients with National Comprehensive Cancer Network (NCCN) unfavorable intermediate- to very-high-risk PCa. Its use led to a management change in 20-30% of patients. However, the effect of these treatment changes on survival outcomes was not clear. Similarly, biomarkers in the pretherapy primary PCa setting increased and decreased the risk, respectively, in 7-30% and 32-36% of NCCN low-risk and 31-65% and 4-15% of NCCN favorable intermediate-risk patients being considered for active surveillance. A change in management was noted in up to 65% of patients, with the change being in line with the molecular risk-based reclassification, but again, the impact of these changes on survival outcomes remained unclear. Notably, in the postsurgical primary PCa setting, biomarker-guided adjuvant radiation therapy (RT) was associated with improved oncological control: Δ↓ 2-yr BCF by 22% (level 2b). In the BCF setting, the data were more mature. PSMA PET was consistently useful in improving disease localization-Δ↑ detection for T, N, and M staging was 13-32%, 19-58%, and 9-29%, respectively. Between 29% and 73% of patients had a change in management. Most importantly, these management changes were associated with improved survival outcomes in three trials: Δ↑ 4-yr disease-free survival by 24.3%, Δ↑ 6-mo metastasis-free survival (MFS) by 46.7%, and Δ↑ androgen deprivation therapy-free survival by 8 mo in patients who received PET-concordant RT (level 1b-2b). Biomarker testing in these patients also appeared to be helpful in risk stratifying and guiding the use of early salvage RT (sRT) and concomitant hormonal therapy. Patients with high-genomic-risk scores benefitted from treatment intensification: Δ↑ 8-yr MFS by 20% with the use of early sRT and Δ↑ 12-yr MFS by 11.2% with the use of hormonal therapy alongside early sRT, while low-genomic-risk score patients did equally well with initial conservative management (level 3). CONCLUSIONS: Both PSMA PET imaging and tumor molecular profiling provide actionable information in the management of men with primary PCa and those with BCF. Emerging data suggest that radiogenomics-guided treatments translate into direct survival benefits for patients, however, additional prospective data are awaited. PATIENT SUMMARY: In this review, we evaluated the utility of prostate-specific membrane antigen positron emission tomography and tumor molecular profiling in guiding the care of men with prostate cancer (PCa). We found that these tests augmented risk stratification, altered management, and improved cancer control in men with a new diagnosis of PCa or for those experiencing a relapse.

Traditional approaches to androgen deprivation therapy.

For most of the past 25 years, 1 of the favored approaches to treating prostate cancer has been the suppression of circulating testosterone with luteinizing hormone-releasing hormone (LHRH) agonists. LHRH agonists produce a downregulation of LHRH receptors and an uncoupling of the LHRH signal transduction mechanism. This leads to a marked reduction in the secretion of bioactive hormones stimulating testosterone production and eventual induction of a reversible, but transient and incomplete, state known as "selective medical hypophysectomy." The treatment with LHRH agonists has proved effective in many settings; however, the dosage and timing strategies depend critically on the patient's disease risk and progression. More recent investigations have suggested that a newer, quicker acting, pure gonadotropin-releasing hormone antagonist might be a preferable treatment approach. It remains a fundamental truth, however, that hormonal therapy is both overused and more toxic than generally appreciated. Therefore, a complete understanding of the indications and applications of this approach is essential for the practice of evidence-based medicine.

Andrographolide, an herbal medicine, inhibits interleukin-6 expression and suppresses prostate cancer cell growth.

Elevated interleukin-6 (IL-6), a major mediator of the inflammatory response, has been implicated in androgen receptor (AR) activation, cellular growth and differentiation, plays important roles in the development and progression of prostate cancer, and is a potential target in cancer therapy. Through drug screening using human prostate cancer cells expressing IL-6 autocrine loop, we found that andrographolide, a diterpenoid lactone isolated from a traditional Chinese and Indian medicinal plant Andrographis paniculata, could inhibit IL-6 expression and suppress IL-6-mediated signals. Andrographolide inhibits IL-6 expression at both mRNA and protein levels in a dose-dependent manner. Andrographolide suppresses both IL-6 autocrine loop- and paracrine loop-induced cell signaling including Stat3 and Erk phosphorylation. Furthermore, andrographolide inhibits cell viability and induces apoptotic cell death in both androgen-stimulated and castration-resistant human prostate cancer cells without causing significant toxicity to normal immortalized prostate epithelial cells. Moreover, treatment of andrographolide to mice bearing castration-resistant DU145 human prostate tumors that express constitutive IL-6 autocrine loop significantly suppresses tumor growth. Taken together, these results demonstrate that andrographolide could be developed as a therapeutic agent to treat both androgen-stimulated and castration-resistant prostate cancer possibly by suppressing IL-6 expression and IL-6-induced signaling.

Renal cell carcinoma: current status and emerging therapies.

Renal cell carcinoma (RCC) accounts for about 3% of all adult malignancies and its incidence is increasing. Smoking, obesity, and end-stage renal disease are important risk factors. Localized RCC may be cured with surgical excision. However, over one-third of patients eventually develop metastatic disease. While chemotherapy and radiation therapy are relatively ineffective for RCC, immunotherapy modestly extends survival and may lead to tumor regression and long-term survival in a small minority of patients. Recently, research into the pathology of genetic syndromes associated with RCC has led to remarkable advances in our understanding of the pathogenesis of sporadic RCC. Rational therapeutic agents developed from this understanding have established new treatment paradigms for this disease.

Outcomes and quality of life issues in the pharmacological management of benign prostatic hyperplasia (BPH).

BACKGROUND: Benign prostatic hyperplasia (BPH) is a common disease of the aging male population. BPH treatment includes a variety of pharmacological and surgical interventions. The goal of this paper is to review the natural history of BPH, outcomes of pharmacological management, effects on quality of life (QoL), future pharmacotherapies, and associated patient-focused perspectives. MATERIALS AND METHODS: Medline searches for the keywords benign prostatic hyperplasia, BPH, alpha blockers, 5 alpha-reductase, and quality of life were performed. Relevant literature was reviewed and analyzed. RESULTS: Alpha blockers, 5 alpha-reductase inhibitors, and phytotherapy are the three categories of pharmaceutical interventions currently available for BPH. Various clinical trials have shown that alpha blockers and 5 alpha-reductase inhibitors are safe, efficacious, and improve QoL in patients with BPH. The evidence for phytotherapeutics is not as convincing. The current armamentarium of pharmaceutical interventions are encompassed in these three classes of medications. New pharmacotherapies based on novel mechanisms are on the horizon. CONCLUSION: There are a variety of safe and efficacious medical therapies available for the management of BPH and it is important for the practicing physician to have an understanding of these pharmacotherapies and their potential impact on the patient. There is not enough evidence to make a recommendation regarding phytotherapy use. New classes of drugs for BPH will likely find their way into routine use.

Minimally invasive therapies for benign prostatic hyperplasia.

A number of minimally invasive therapies have been studied in the last decade for the treatment of lower urinary tract symptoms due to benign prostatic hyperplasia (BPH). Most of these utilize thermal energy to ablate the prostate. Paucity of long-term efficacy, safety and re-treatment rates are, however, the main concerns of all these forms of treatment. Minimally invasive therapies can be positioned between pharmacotherapy and transurethral resection of the prostate (TURP). Studies have shown that some of these therapies stand the test of time, with low and acceptable re-treatment rates and shorter hospital stay. Therapies such as transurethral needle ablation (TUNA) and high energy transurethral microwave thermotherapy (HE-TUMT) effectively relieve symptoms with less morbidity. Laser prostatectomy is less commonly used due to the slow and difficult resection/vaporization. Minimally invasive therapies are particularly useful in those on anticoagulants, in whom anesthesia is contraindicated and younger men with an active sex life. However, these devices have not been compared with TURP in large-scale controlled trials and, therefore, will not be able to replace TURP until their long-term durability of symptom relief is known.