Role of immunotherapy for renal cell cancer in 2011.

High-dose interleukin-2 (IL-2) and interferon were the most commonly administered therapies before the recent introduction of targeted agents, including vascular endothelial growth factor and mammalian target of rapamycin pathway inhibitors. Although the new agents result in a progression-free survival benefit, high-dose IL-2 remains the only agent with proven efficacy in producing durable complete and partial responses in patients with metastatic renal cell carcinoma (RCC). Furthermore, although the use of single-agent interferon has decreased significantly since the introduction of targeted therapy, it remains in the frontline setting in combination with bevacizumab as a result of 2 large phase III trials.

Immunoexpression status and prognostic value of mTOR and hypoxia-induced pathway members in primary and metastatic clear cell renal cell carcinomas.

The need for effective targeted therapies for renal cell carcinomas (RCCs) has fueled the interest for understanding molecular pathways involved in the oncogenesis of kidney tumors. Aiming to analyze the expression status and prognostic significance of mTOR and hypoxia-induced pathway members in patients with clear cell RCC (ccRCC), tissue microarrays were constructed from 135 primary and 41 metastatic ccRCCs. Immunoexpression levels were compared and correlated with clinicopathologic parameters and outcome.

A non-comparative randomized phase II study of 2 doses of ATN-224, a copper/zinc superoxide dismutase inhibitor, in patients with biochemically recurrent hormone-naïve prostate cancer.

Objective: ATN-224 (choline tetrathiomolybdate) is an oral Cu(2+)/Zn(2+)-superoxide dismutase 1 (SOD1) inhibitor with preclinical antitumor activity. We hypothesized that ATN-224 may induce antitumor effects as an antiangiogenic agent at low dose-levels while possessing direct antitumor activity at higher dose-levels. The objective of this study was to screen its clinical activity in patients with biochemically recurrent hormone-naïve prostate cancer.

Eastern Cooperative Oncology Group Phase II Trial of lapatinib in men with biochemically relapsed, androgen dependent prostate cancer.

Purpose: Activation of the epidermal growth factor pathway is important in prostate cancer development and the transcription of androgen receptor regulated genes. This study evaluated the potential activity of lapatinib in men with biochemically-relapsed androgen-dependent (stage D0) prostate cancer.

Patients And Methods: Patients with a rising PSA after primary therapy for prostate cancer were enrolled.

The natural history of metastatic progression in men with prostate-specific antigen recurrence after radical prostatectomy: long-term follow-up.

Objective: To describe metastasis-free survival (MFS) in men with prostate-specific antigen (PSA) recurrence following radical prostatectomy, and to define clinical prognostic factors modifying metastatic risk.

Patients And Methods: We conducted a retrospective analysis of 450 men treated with prostatectomy at a tertiary hospital between July 1981 and July 2010 who developed PSA recurrence (≥0.2 ng/mL) and never received adjuvant or salvage therapy before the development of metastatic disease.

Lenalidomide modulates IL-8 and anti-prostate antibody levels in men with biochemically recurrent prostate cancer.

Background: We retrospectively explored changes in immunological parameters in men with biochemically recurrent prostate cancer treated with either 5 or 25 mg of lenalidomide in a randomized phase 2 trial, and determined whether those changes correlated with disease progression.

Methods: Cytokine levels were compared for each patient at baseline and after 6 months of treatment with lenalidomide. Regression models for correlated data were used to assess associations of cytokine levels with lenalidomide treatment effect.

Contemporary experience with ketoconazole in patients with metastatic castration-resistant prostate cancer: clinical factors associated with PSA response and disease progression.

Background: Adrenal/intratumoral androgen biosynthesis contributes to ligand-dependent androgen receptor activation in metastatic castration-resistant prostate cancer (mCRCP). Compounds targeting CYP-17 hydroxylase and lyase, as ketoconazole and abiraterone, block adrenal/intratumoral androgen biosynthesis, and are used as sequential endocrine approaches in mCRCP. We aimed to describe contemporary experience and association of clinical factors with Prostate specific antigen (PSA) response and disease progression, in mCRPC progressing on GnRH-agonist, antiandrogen, antiandrogen withdrawal, and treated with ketoconazole.

Angiotensin system inhibitors and outcome of sunitinib treatment in patients with metastatic renal cell carcinoma: a retrospective examination.

Background: Sunitinib is a standard treatment for metastatic renal cell carcinoma. Angiotensin system inhibitors, including angiotensin converting enzyme inhibitors and angiotensin II receptor blockers, are widely used in hypertension, kidney disease and heart failure. Data suggests that they may inhibit tumourigenesis.

New therapies for castration-resistant prostate cancer: efficacy and safety.

Context: Prostate cancer (PCa) is the most common noncutaneous malignancy and the second leading cause of cancer mortality amongst men in the Western world. Up to 40% of men diagnosed with PCa will eventually develop metastatic disease, and although most respond to initial medical or surgical castration, progression to castration resistance is universal. The average survival for patients with castration-resistant prostate cancer (CRPC) is 2-3 yr.

NCCN Task Force report: optimizing treatment of advanced renal cell carcinoma with molecular targeted therapy.

The outcome of patients with metastatic renal cell carcinoma has been substantially improved with administration of the currently available molecularly targeted therapies. However, proper selection of therapy and management of toxicities remain challenging. NCCN convened a multidisciplinary task force panel to address the clinical issues associated with these therapies in attempt to help practicing oncologists optimize patient outcomes.

Preventive care in prostate cancer patients: following diagnosis and for five-year survivors.

Introduction: Prostate cancer is the most common male cancer. Survival rates are high, making preventive care maintenance important. Factors associated with prostate-cancer cases' preventive care in the short-term (Year 1) and long-term (Year 5), and how survivors' care compares to non-cancer controls, require study.

Once-daily dasatinib: expansion of phase II study evaluating safety and efficacy of dasatinib in patients with metastatic castration-resistant prostate cancer.

Objectives: To determine the activity and tolerability of 100-mg once-daily (QD) dasatinib in patients with metastatic castration-resistance prostate cancer (CRPC). Dasatinib, an oral Src family kinase inhibitor, has demonstrated both preclinical and clinical activity with twice-daily dosing in patients with metastatic CRPC.

Methods: Chemotherapy-naive men with metastatic CRPC and increasing prostate-specific antigen levels were treated with dasatinib 100 mg QD.

The change of PSA doubling time and its association with disease progression in patients with biochemically relapsed prostate cancer treated with intermittent androgen deprivation.

Background: We sought to determine the change of PSA doubling time (PSADT) and its association with disease progression during intermittent androgen deprivation (IAD) therapy for prostate cancer.

Methods: Data were retrospectively analyzed in 96 patients with biochemically relapsed prostate cancer (BRPC) treated with IAD since 1995. IAD consisted of LHRH-agonists ± antiandrogen given usually at PSA threshold (ng/ml) of 10-20, for 6-9 months.

Effects of a problem-solving intervention (COPE) on quality of life for patients with advanced cancer on clinical trials and their caregivers: simultaneous care educational intervention (SCEI): linking palliation and clinical trials.

Context: Patients on investigational clinical trials and their caregivers experience poor quality of life (QOL), which declines as the disease progresses.

Objective: To examine the effect of a standardized cognitive-behavioral problem-solving educational intervention on the QOL of patients enrolled on investigational clinical trials and their caregivers.

Design: Prospective, multi-institution, randomized trial.

Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study.

Background: Bone metastases are a major burden in men with advanced prostate cancer. We compared denosumab, a human monoclonal antibody against RANKL, with zoledronic acid for prevention of skeletal-related events in men with bone metastases from castration-resistant prostate cancer.

Methods: In this phase 3 study, men with castration-resistant prostate cancer and no previous exposure to intravenous bisphosphonate were enrolled from 342 centres in 39 countries.

Can patient-reported outcome measures identify cancer patients' most bothersome issues?

Purpose: Patient-reported outcome (PRO) questionnaires are being investigated for their ability to aid in individual patient management. We evaluated whether PROs can identify patients' most bothersome quality-of-life issues and compared approaches for interpreting PRO scores.

Methods: This secondary data analysis included 130 patients with cancer (mean age, 57 years; 71% female) receiving outpatient palliative chemotherapy.

Future directions in castrate-resistant prostate cancer therapy.

Although several new therapies have recently become available for the treatment of castrate-resistant prostate cancer (CRPC), the disease remains universally incurable and demands novel therapeutic approaches. To this end, great strides have been made in our understanding of the biologic and molecular mechanisms driving prostate cancer growth and progression in the past few years, resulting in widespread clinical investigation of numerous new targeted therapies. This review will highlight some of the key therapeutic agents that (in the opinion of the authors) may have the largest effect on the future management of CRPC, with a focus on both molecular targets and clinical trial design.

Phase I trial of oxaliplatin, infusional 5-fluorouracil, and leucovorin (FOLFOX4) with erlotinib and bevacizumab in colorectal cancer.

Rationale: This phase I study was conducted to determine the maximum tolerated dose (MTD) of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, with 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX4) in patients with advanced colorectal cancer (CRC). Bevacizumab was later included as standard of care at the MTD.

Patients And Methods: Patients received FOLFOX4 with escalating doses of erlotinib: dose level (DL) 1, 50 mg; DL 2, 100 mg; and DL 3, 150 mg once daily continuously.

A phase II study of 2-methoxyestradiol nanocrystal colloidal dispersion alone and in combination with sunitinib malate in patients with metastatic renal cell carcinoma progressing on sunitinib malate.

Background: Current treatment for metastatic renal cell cancer with vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKI) have provided improved overall survival, but complete responses are rare. We conducted a multicenter phase II study to evaluate the objective response rate of 2-methoxyestradiol (2ME2 NCD) alone and in combination with sunitinib for patients with metastatic renal cell carcinoma who have progressed on sunitinib alone.

Methods: Adults with metastatic kidney cancer were stratified depending on whether they were still taking sunitinib or had discontinued sunitinib therapy at the time of registration.

Phase I dose-escalation study of the novel antiandrogen BMS-641988 in patients with castration-resistant prostate cancer.

Purpose: BMS-641988 is an androgen receptor antagonist with increased potency relative to bicalutamide in both in vitro and in vivo prostate cancer models. A first-in-man phase I study was conducted to define the safety and tolerability of oral BMS-641988 in patients with castration-resistant prostate cancer (CRPC).

Experimental Design: Doses were escalated from 5 to 150 mg based on discrete pharmacokinetic parameters in cohorts of three to six subjects.

Phase II study of cilengitide (EMD 121974, NSC 707544) in patients with non-metastatic castration resistant prostate cancer, NCI-6735. A study by the DOD/PCF prostate cancer clinical trials consortium.

Background: Integrins mediate invasion and angiogenesis in prostate cancer bone metastases. We conducted a phase II study of cilengitide, a selective antagonist of α(v)β(3) and α(v)β(5) integrins, in non-metastatic castration resistant prostate cancer with rising PSA.

Methods: Patients were observed for 4 weeks with PSA monitoring, and then treated with 2,000 mg IV of cilengitide twice weekly until toxicity/progression.

Does valproic acid induce neuroendocrine differentiation in prostate cancer?

Valproic Acid (VPA) is a histone deacetylase inhibitor that holds promise for cancer therapy. Here, we investigate whether VPA treatment induces neuroendocrine differentiation of Prostate Cancer (PCa). A tissue microarray of VPA-treated and untreated tumor xenografts and cell lines of human PCa (LNCaP, C4-2, DU145, and PC-3) were generated and were analyzed by immunohistochemical analysis (IHC) for NE markers chromogranin A (CgA), synaptophysin, and NCAM (neural cell adhesion molecule).

Lenalidomide in nonmetastatic biochemically relapsed prostate cancer: results of a phase I/II double-blinded, randomized study.

Purpose: To evaluate the safety and activity of 6 months of treatment with lenalidomide at 5 or 25 mg/d in nonmetastatic biochemically relapsed prostate cancer.

Experimental Design: Sixty men with non-castrate, nonmetastatic, biochemically relapsed prostate cancer were stratified by prostate-specific antigen (PSA) doubling time, surgery/radiation therapy, prior androgen deprivation therapy (ADT), and randomized to lenalidomide 5 mg (n = 26) or 25 mg/d (n = 34) for 3 weeks repeated monthly for 6 months or until dose-limiting toxicity or disease progression. Toxicity was evaluated monthly, and PSAs and X-rays/scans every 6 months.

Castration-dependent pharmacokinetics of docetaxel in patients with prostate cancer.

Purpose: To assess whether the low incidence of severe neutropenia in castrated men with prostate cancer treated with docetaxel is the result of changes in systemic clearance.

Patients And Methods: A total of 10 noncastrated and 20 castrated men with prostate cancer were studied to achieve 80% power (α = .05) to detect at least a 25% change in the clearance of docetaxel.