The role of luteinizing hormone-releasing hormone therapy in locally advanced prostate cancer and biochemical failure: considerations for optimal use

BACKGROUND: More patients are being diagnosed with prostate cancer at an earlier age with earlier stage disease because of advances in screening and detection. Investigators continue to explore the use of hormone therapy, particularly luteinizing hormone-releasing hormone (LHRH) analogues, earlier in the course of disease. OBJECTIVE: This review summarizes clinical evidence regarding the safety and efficacy of LHRH analogues in the treatment of locoregional disease or following biochemical failure. METHODS: Relevant information from clinical studies was identified through a MEDLINE search of the medical literature published in English in the last 5 years (search terms: LHRH and prostate cancer). The search included prospective and retrospective clinical studies on LHRH therapy in locally advanced prostate cancer. Additional relevant publications published before 1999 were identified from citations in the resulting articles. RESULTS: The available clinical evidence suggests that the use of LHRH analogues as adjuvant or neoadjuvant therapy in conjunction with radiation therapy may improve survival outcomes. Few studies have evaluated the use of LHRH analogues after biochemical failure. However, several related studies indicate that initiating hormone therapy earlier rather than later may provide some clinical benefit. When considering early initiation of LHRH therapy, the potential risks of long-term treatment must be considered. Physiologic changes, such as deterioration of body composition and bone quality, may have important effects on the risk of developing cardiovascular disease and osteoporosis. CONCLUSIONS: Although some clinical evidence supports the use of LHRH analogues as adjuvant or neoadjuvant therapy or following biochemical failure, further study is needed. In the meantime, clinicians should carefully weigh the potential benefits and risks of early hormone therapy when making treatment decisions.     

The evolving role of hormone therapy in advanced prostate cancer

Earlier diagnosis and treatment of prostate cancer has changed the face of late-stage disease, and the use of mainstay hormonal therapies--orchiectomy, luteinizing hormone releasing-hormone analogs, and combined androgen ablation--are evolving rapidly. New approaches such as antiandrogen monotherapy and intermittent therapy are being evaluated. In addition, palliative treatments for patients with androgen-independent tumors have expanded. The most common clinical presentation of advanced prostate cancer is a rising prostate-specific antigen level following primary therapy (radical prostatectomy or radiotherapy or both). Due to the negative psychological implications of orchiectomy, many patients are opting for treatment with luteinizing hormone-releasing hormone analogs. Because studies of combined androgen ablation have not provided conclusive results, it is reasonable to forego antiandrogen therapy for patients who undergo bilateral orchiectomy. Management options for patients with androgen-independent prostate cancer are expanding and include antiandrogen removal, antiandrogen therapy, and glucocorticoids.     

Significance of a decline in bone mineral density while receiving oral bisphosphonate treatment

BACKGROUND: Oral bisphosphonates are routinely prescribed for the treatment of postmenopausal osteoporosis. In clinical trials, oral bisphosphonates have been found to increase bone mineral density (BMD) and decrease fracture risk in the majority of the treated population. However, in both clinical trials and clinical practice, not all patients experience significant increases in BMD. In clinical trials, nonresponse is often defined as a BMD change of 相似文献   

The role of surgery in the treatment of prostate cancer

OBJECTIVES: To describe the role of surgery in the treatment of organ-confined prostate cancer and advanced prostate cancer. DATA SOURCES: Journals, textbooks, and personal communication. CONCLUSIONS: Radical prostatectomy plays a possible role in curing those patients with disease confined to the prostate. Bilateral orchiectomy plays a palliative role for patients with advanced disease. IMPLICATIONS FOR NURSING PRACTICE: This article provides nurses with the knowledge needed to teach patients about how the surgery is performed, the associated complications, and the likelihood of cancer control.     

Effect of miglustat on bone disease in adults with type 1 Gaucher disease: a pooled analysis of three multinational, open-label studies

BACKGROUND: Bone manifestations are a source of disability among patients with Gaucher disease (GD) and a focus of disease management. The effect of enzyme replacement therapy (ERT) on GD bone disease can be limited and may take up to 8 years to become manifest. Miglustat, a glucosylceramide synthase inhibitor, may have a positive influence on GD bone disease. OBJECTIVES: The aim of this analysis was to evaluate the effects of miglustat on bone manifestations and bone mineral density (BMD) in patients with type 1 GD. METHODS: This was a pooled analysis of data collected prospectively over an observation period of 2 years from patients who participated in 3 multinational, open-label clinical trials evaluating the efficacy and tolerability of miglustat 100 mg TID (the currently approved therapeutic dose). Bone manifestations were assessed qualitatively and in relation to treatment and spleen status. The effects of miglustat on BMD were assessed by dual-energy x-ray absorptiometry at the lumbar spine and/or femoral neck. Bone response was defined as a positive change in BMD, based on the change in BMD Z-score from baseline to months 6, 12, and 24. Changes in BMD were also analyzed according to spleen status and baseline severity of osteopenia. RESULTS: The analysis involved 72 patients, including 41 (57%) who had received previous ERT and 20 (28%) who had undergone splenectomy. Patients' mean (SD) age was 41.2 (13.1) years. The most frequent bone-related manifestations at study entry were osteoporosis (43/63 [68%] patients) and bone pain (41/65 [63%] patients). At 2 years, 54/65 (83%) patients reported no bone pain. The reductions in bone pain were comparable among all subgroups, including high-risk patients (ie, splenectomized). No new cases of bone crisis, avascular necrosis, or pathologic fractures were reported. BMD Z-scores were improved from baseline at both the lumbar spine and femoral neck at each time point (months 6, 12, and 24) (P < 0.001). As early as 6 months after the initiation of miglustat monotherapy, significant increases from baseline in the BMD Z-score were observed at both the lumbar spine (mean, 0.15; P = 0.022) and femoral neck (0.23; P < 0.001); the increases remained significant at 12 months (0.19 [P = 0.012] and 0.21 [P = 0.017], respectively) and 24 months (0.21 [P = 0.015] and 0.18 [P = 0.039]). Significant increases in BMD Z-scores were observed at the femoral neck in splenectomized patients (P < 0.001) and at both sites in osteoporotic patients (lumbar spine: P < 0.001; femoral neck: P = 0.006). CONCLUSION: This pooled analysis of 3 open-label studies of miglustat 100 mg TID suggests that miglustat monotherapy may reduce the incidence of bone pain and improve BMD in patients with type 1 GD, including those with a history of splenectomy and/or osteoporosis.     

Evidence-based medical perspectives: the evolving role of PSA for early detection, monitoring of treatment response, and as a surrogate end point of efficacy for interventions in men with different clinical risk states for the prevention and progression of prostate cancer

Following FDA approval and introduction into the clinic in the mid-1980s, PSA testing has become arguably the most versatile serum tumor marker in urologic oncology with clinical use for early detection (screening) of prostate cancer (PC), risk stratification for clinical staging, prognosis, intermediate biomarker for monitoring tumor recurrence, and more recently as an intermediate biomarker for assessing therapeutic response to antiandrogens, radiation therapy, and chemotherapy. PSA now routinely guides health care providers for the clinical management of PC over a wide range of clinical risk states for men at risk of PC, after local definitive therapy and after systemic therapy to prevent progression to metastatic bone disease, and to palliate men with hormone refractory prostate cancer (HRPC). To further assess the evidence that supports these clinical applications, this commentary reviews and critically evaluates the emerging body of new data focusing on several recently published seminal articles by D'Amico et al and Thompson et al, the new National Comprehensive Cancer Network 2004 recommendations for starting PSA testing at the age of 40 years old, the latest results from 2 phase 3 randomized, controlled trials of taxane-based regimens showing improved survival for men with HRPC, and the recent US FDA Public Workshop on Clinical Trial Endpoints in Prostate Cancer that helped to distill and synthesize the current state of the art and the progress toward validation of PSA metrics (eg, PSA velocity) as a surrogate end point (SE) for treatment efficacy with taxane-based regimens. Furthermore, several randomized, controlled chemoprevention trials in progress evaluating agents such as selenium and vitamin E in high-risk cohorts are well poised to confirm the validity of PSA as an SE for clinical efficacy for the prevention and progression of PC. Although there continues to be a need to validate better biomarkers before diagnosis of PC (more sensitive and specific) and after diagnosis to discern between indolent and aggressive forms of PC, it is very likely that some metric of PSA as a biomarker alone or as part of a panel of other serum proteomic markers or tissue-derived multiplex gene expression arrays will be around for years to come as a useful tool for risk stratification, early detection, prognosis, prediction, and as an SE of efficacy for prevention and treatment of PC.     

Optimizing the management of postmenopausal osteoporosis with bisphosphonates: the emerging role of intermittent therapy

BACKGROUND: The utility of bisphosphonates in the treatment of postmenopausal osteoporosis is compromised by the requirement of frequent oral administration or complex cyclic regimens. Recognition that simplified dosing regimens and reduced frequency of administration are important factors for improving adherence to therapy has led to the development of bisphosphonates with less frequent dosing regimens that aim to offer greater convenience. OBJECTIVE: This paper reviews the available data concerning the efficacy and tolerability of intermittent (less frequent than weekly) bisphosphonate dosing regimens for the treatment of postmenopausal osteoporosis, with particular focus on the potential implications for clinical management. METHODS: Papers on intermittent or cyclic bisphosphonate dosing regimens were identified by searching MEDLINE using the following terms: dose, dosing, dosage, or drug therapy; intermittent, cyclic, cyclical, weekly, monthly, month, week, administration, regimen, or schedule; and etidronate, alendronate, risedronate, zoledronate, neridronate, pamidronate, clodronate, ibandronate, or tiludronate. RESULTS: Because the currently available bisphosphonates differ in chemical structure, potency, and other physicochemical and biologic characteristics, comparable dose-free intervals may not be appropriate for all drugs. Several bisphosphonates have demonstrated efficacy in terms of an increase in bone mineral density (BMD) and a decrease in markers of bone turnover when administered intermittently. However, evidence of fracture benefit from a less frequent bisphosphonate dosing regimen was demonstrated recently. The nitrogen-containing bisphosphonate ibandronate was associated with a significant decrease in vertebral fracture risk when administered as an intermittent dosing regimen (P < 0.001 vs placebo). This study supports the concept that bisphosphonates such as ibandronate can be effectively administered less frequently than daily or weekly. CONCLUSIONS: Bisphosphonate therapy using intermittent schedules with between-dose intervals longer than 1 week is capable of reducing the risk of fracture, improving BMD, and suppressing biochemical markers of bone turnover. Planned and ongoing trials will determine the place of intermittent bisphosphonates in the treatment algorithm for postmenopausal osteoporosis.     

Systemic bias in the medical literature on androgen deprivation therapy and its implication to clinical practice

Background: LHRH agonists are used for androgen deprivation therapy (ADT) to treat prostate cancer, but have many side effects that reduce of the quality of life of prostate cancer patients and their partners. Patients are poorly informed about the side effects of these drugs and how to manage them. Aim: To test the hypothesis that there is bias in the peer‐reviewed literature on ADT that correlates with an association between authors and the luteinising hormone‐releasing hormone (LHRH) agonists pharmaceutical industry. Methods: We assessed 155 articles on ADT published in English‐language peer‐reviewed journals in terms of how comprehensive they were in acknowledging LHRH agonists’ side effects. Results: Although the literature regarding ADT is substantial, the vast majority of articles failed to acknowledge many of the more stressful side effects of ADT for patients and their partners. Articles most likely to acknowledge the psychosocial impact of ADT were significantly less likely to have had industrial support than those articles that did not mention those side effects. Alternative treatments to the LHRH agonists were rarely mentioned. Authors who indicated some association with a pharmaceutical company tended to minimise the side effects of LHRH agonists and not acknowledge alternatives to the LHRH agonists for ADT. Conclusion: Industrial support is associated with a proliferation of articles published in the peer‐reviewed literature directed at practising physicians. Such flooding of the literature may, in part, limit physicians’ knowledge of the side effects of these drugs and, in turn, account for the poor knowledge that patients on LHRH agonists have about the drugs they are taking and ways to manage their side effects.     

Erlotinib: small-molecule targeted therapy in the treatment of non-small-cell lung cancer

BACKGROUND: Erlotinib is an oral tyrosine kinase inhibitor, targeting the human epidermal receptor type 1/ epidermal growth factor receptor, recently approved by the US Food and Drug Administration (FDA) for the treatment of patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) after the failure of more than 1 or 2 previous chemotherapeutic regimens. OBJECTIVE: The purpose of this article is to summarize the development, pharmacology, pharmacokinetics, efficacy, and adverse effects of erlotinib. METHODS: A literature search was conducted with the MEDLINE and EMBASE (1999-2005) databases using the search terms non-small-cell lung cancer, erlotinib, and epidermal growth factor receptor inhibitor. Abstracts from the American Society of Clinical Oncology and documents submitted to the FDA also were reviewed. RESULTS: BR.21, a randomized, placebo-controlled, multinational Phase III trial demonstrated clinically and statistically improved overall survival in patients with advanced or metastatic NSCLC treated with erlotinib versus placebo as second-line therapy. The erlotinib group had a median survival of 6.7 months versus a median survival of 4.7 months in the placebo group (P < 0.001). The toxicity profile of erlotinib was moderately benign, with the most commonly documented adverse events requiring dose reductions including skin rash (12%) and diarrhea (5%). Interstitial lung disease and relative fatalities were reported infrequently (0.8%) in patients receiving erlotinib. Two randomized, placebo-controlled, multicenter Phase III trials conducted in patients with locally advanced and metastatic NSCLC showed no clinical benefit with first-line administration of erlotinib plus concurrent platinum-based chemotherapy. CONCLUSIONS: For patients with NSCLC in whom more than 1 or 2 previous chemotherapeutic regimens have failed, erlotinib is an effective therapy with significant overall survival benefits. The use of erlotinib as first-line therapy in combination with platinum-based chemotherapeutic regimens, however, has failed to demonstrate efficacy in the treatment of NSCLC.     

Immunotherapy for prostate cancer - recent progress in clinical trials

Prostate cancer is the most common malignancy affecting men in the United States. Traditional therapy with radical prostatectomy or radiation therapy can be curative for localized disease, but metastatic prostate cancer is currently incurable. The only treatments known to prolong survival in patients with metastatic disease are androgen-deprivation therapy and chemotherapy, both of which have significant side effects. Immunotherapy approaches offer hope in providing new treatments to delay disease progression, ideally with fewer side effects. The results from nearly all early immunotherapy clinical trials for prostate cancer conducted to date have shown minimal toxicity, and many have suggested clinical benefit in terms of delaying disease progression. Several phase III clinical trials are currently under way in patients with metastatic, androgen-independent prostate cancer. The current article reviews recent trials evaluating immune-modulating agents, antigen-specific active immunotherapy, and combination therapies in clinical development for the treatment of prostate cancer.     

A review of mitomycin regimens in advanced breast cancer therapy

Mitomycin is one of the most effective single agents in the treatment of advanced breast cancer. Recent studies have also shown that combination regimens including mitomycin are effective as initial therapy in advanced breast cancer. In patients with advanced disease who fail to respond to initial chemotherapy, a combination regimen including mitomycin is as effective as the other combinations currently used in salvage therapy. A combination of mitomycin and a drug such as doxorubicin or vinblastine produces results equivalent to those reported with regimens more commonly used. Such a combination is a therapeutic alternative in patients with advanced breast cancer.     

LH-RH-endocrine manipulation in cancer of the prostate

The treatment of advanced stage D, cancer of the prostate is palliative, and based mainly on endocrine manipulations: orchiectomy or estrogen administration. Both attempt to achieve objective and subjective patient response by reducing either the amount or the action of circulating testosterone levels. This review discusses the history and rationale of these endocrine treatments. Two long term clinical studies completed during the 1950's and 1960's have shown the beneficial effects of estrogen use on patient survival. Despite several design errors, these studies indicated favorable results obtained by the combined use of orchiectomy and estrogens in producing long-term remissions. Recently, advances made in the use of hormone-receptor analysis have been applied to the selection of patients who may benefit from various forms of endocrine treatment. The application of these techniques stems from the encouraging results obtained with the use of receptor analysis in the management of advanced carcinomas of the breast, also a hormone-responsive tumor. Preliminary reports are encouraging as patient selection may be accomplished more rationally, while sparing potential non-responders the side-effects of long-term estrogen administration. The role of the recently available luteinizing hormone releasing hormone (LHRH) analogues as diagnostic and therapeutic tools in the treatment of advanced prostatic carcinoma is also discussed.     

Effect of teriparatide on bone mineral density and fracture in postmenopausal osteoporosis: meta-analysis of randomised controlled trials

To determine the efficacy of teriparatide supplementation for improving bone mineral density (BMD) and fracture risk in postmenopausal osteoporosis and if effects vary with factors. We identified eight randomised controlled trials (n = 2388) using electronic databases, supplemented by a hand-search of the reference lists. All trials aimed to evaluate the efficacy of daily subcutaneous teriparatide injection in postmenopausal osteoporosis. The main outcomes were fracture risk and percentage change of BMD from baseline. Data were pooled by employing a random-effect model. In trials that reported BMD as an outcome, treatment was associated with an increase of bone mass of 8.14% [95% confidence interval (CI): 6.72-9.55%; eight trials, n = 2206] in spine and 2.48% (95% CI: 1.67-3.29%; seven trials, n = 1303) at the hip. In trials that reported fracture as an outcome, treatment was associated with a 70% risk reduction in vertebral fractures (risk ratio 0.30, 95% CI: 0.21-0.44; three trials, n = 1452) and 38% risk reduction in non-vertebral fractures (risk ratio 0.62, 95% CI: 0.44-0.87; three trials, n = 1842). The PTH treatment with total calcium intake more than 1500 mg was related to a significant increase in BMD gains at total hip (1.40% vs. 3.72%; p = 0.004). However, long-term duration did not appear to contribute to differences in responsiveness to teriparatide. Evidence supports the use of teriparatide in treatment of women with postmenopausal osteoporosis who are at risk for fracture. Further studies directly comparing concurrent therapy and calcium supplement with long-term duration are warranted.     

Zoledronic acid in the management of metastatic bone disease

Bisphosphonate therapy has become a standard of therapy for patients with malignant bone disease. Moreover, in vivo preclinical and preliminary clinical data suggest that bisphosphonates may prevent cancer treatment-induced bone loss and the onset of malignant bone disease in patients with early-stage cancer. This comprehensive review critically reports the several preclinical evidences of action of bisphosphonates on osteoclasts, lymphocytes and tumour cells. In addition, all the clinical trials evaluating the effects of principal bisphosphonates on skeletal disease progression in patients with breast cancer, prostate cancer, non-small cell lung cancer and other cancers have been reported. Of the available bisphosphonates, intravenous zoledronic acid has demonstrated the broadest clinical activity and is actually approved for the treatment of bone metastases from any solid tumour in many countries. Renal safety is an important consideration for oncologists who are treating patients with bisphosphonates. This issue and the other topics relating to the safety of bisphosphonates are discussed in this review.     

Zoledronic acid in the management of metastatic bone disease

Bisphosphonate therapy has become a standard of therapy for patients with malignant bone disease. Moreover, in vivo preclinical and preliminary clinical data suggest that bisphosphonates may prevent cancer treatment-induced bone loss and the onset of malignant bone disease in patients with early-stage cancer. This comprehensive review critically reports the several preclinical evidences of action of bisphosphonates on osteoclasts, lymphocytes and tumour cells. In addition, all the clinical trials evaluating the effects of principal bisphosphonates on skeletal disease progression in patients with breast cancer, prostate cancer, non-small cell lung cancer and other cancers have been reported. Of the available bisphosphonates, intravenous zoledronic acid has demonstrated the broadest clinical activity and is actually approved for the treatment of bone metastases from any solid tumour in many countries. Renal safety is an important consideration for oncologists who are treating patients with bisphosphonates. This issue and the other topics relating to the safety of bisphosphonates are discussed in this review.     

Fluorescence in situ hybridization aneuploidy as a predictor of clinical disease recurrence and prostate-specific antigen level 3 years after radical prostatectomy

OBJECTIVE: To determine if fluorescence in situ hybridization (FISH) analysis of fresh-tissue biopsy specimens obtained at the time of radical prostatectomy is able to predict prospectively clinical disease progression or prostate-specific antigen (PSA) level in patients 3 to 4 years after surgery. MATERIALS AND METHODS: FISH analysis was performed on fresh-tissue touch preparations obtained from 90 randomly selected radical prostatectomy specimens. Cut surface touch preparations from 40 specimens resected in 1992 were analyzed with DNA probes for chromosomes 4, 6-12, 17, 18, X, and Y. Needle-biopsy specimens were obtained from 50 tumors resected in 1993, and touch preparations from these specimens were studied with DNA probes for chromosomes 7, 8, 11, and 12. Serum PSA levels and clinicopathologic data were recorded, and each patient was followed up from the time of surgery to determine cancer progression. RESULTS: Of 90 patients undergoing radical prostatectomy in 1992 and 1993, 89 returned for follow-up. Three patients received preoperative hormonal therapy, and in 2 patients, antiandrogen therapy was continued postoperatively. Fifteen patients underwent intraoperative orchiectomy immediately after radical prostatectomy, while 9 patients had postoperative adjuvant hormonal therapy. Six patients underwent postoperative radiation therapy. Fourteen patients (15.7%) demonstrated systemic, local, or PSA progression. Only 2 (4.7%) of 43 patients with FISH diploid tumors demonstrated cancer progression. Conversely, 10 (30.3%) of 33 FISH aneuploid and 12 (26.1%) of 46 FISH nondiploid tumors demonstrated cancer progression (P=.004 and P=.006, respectively). Unlike FISH, flow cytometric aneuploidy was not associated with early cancer progression. Elevated preoperative PSA concentration, increased preoperative and postoperative Gleason score, and increased preoperative and postoperative T or N stage were not statistically significantly associated with cancer progression. While chromosome 7 and 8 aneusomies were not statistically associated with cancer progression, 2 of 5 (P=.04) chromosome 12 aneusomic tumors demonstrated cancer progression. CONCLUSION: Early (within 4 years) local, systemic, or PSA progression occurred more frequently (P<.05) in radical prostatectomy patients with FISH aneuploid, nondiploid, and chromosome 12 aneusomic tumors. Flow cytometric ploidy status, preoperative serum PSA concentration, and clinical or pathologic grade or stage, including seminal vesicle involvement, margin status, and capsular perforation status, were not associated with early prostate cancer progression in this group of 89 patients. FISH analysis appears to be a useful preoperative tool for predicting aggressive vs indolent prostate cancer.     

Trends and Racial Differences in the Use of Androgen Deprivation Therapy for Metastatic Prostate Cancer

ContextAndrogen deprivation therapy (ADT) is widely used to manage the symptoms of advanced prostate cancer and has been shown to slow the progression of the disease. Previous research investigating racial differences in the use of ADT has reported inconsistent findings.ObjectivesThe purpose of this study was to assess use trends for ADT overall and by type (orchiectomy and luteinizing hormone-releasing hormone [LHRH] agonists) and the factors associated with time to receipt for metastatic prostate cancer.MethodsData from the Surveillance, Epidemiology, and End Results (SEER) cancer registry and Medicare claims database were obtained for 5,273 men, aged 65 years and older and diagnosed with Stage IV prostate cancer during 1991–1999 from seven SEER regions. An accelerated failure time regression model with log-normal distribution was used to examine factors associated with mean time to receipt of ADT.ResultsAfrican-American men were less likely than white men to receive any ADT after diagnosis (P < 0.001). Differences were noted in the time to receipt of ADT, with African-American men having a longer mean time to receipt of orchiectomy (time ratio [TR] = 1.50; 95% confidence interval [CI] = 1.03, 2.17) or LHRH agonist (TR = 1.42; 95% CI = 1.06, 1.89) than white men.ConclusionAfrican-American men with metastatic prostate cancer were significantly less likely to receive ADT and, when treated, had a slightly longer time to receipt than white men, which has implications for patients and physicians involved in the palliative management of metastatic prostate cancer.     

Management of Advanced Penile Cancer

Penile squamous cell carcinoma (PSCC) is a rare cancer, with approximately 2000 new cases in the United States and 35,000 globally every year. Multiple risk factors are involved in PSCC, but most importantly, the high-risk human papillomavirus infection is thought to be present in approximately 50% of cases. Penile squamous cell carcinoma presents as localized or locally advanced disease. Multiple prognostic markers have been explored over the past 3 decades, but lymph node status remains the strongest predictor of clinical outcomes. Surgical decisions are based on the primary tumor pathologic findings, nodal clinical examination, and imaging results. Most patients with high-risk advanced PSCC benefit from a multimodal treatment approach combining chemotherapy with consolidation surgical treatment. The role of neoadjuvant chemotherapy with radiation therapy has not been well explored in PSCC. Prospective clinical studies, like the International Penile Advanced Cancer Trial, have been launched to provide high-level evidence for multimodal treatment. The International Penile Advanced Cancer Trial is the first randomized clinical trial among patients with PSCC and is currently accruing, with the expectation to generate results in 2023. Unfortunately, most patients with high-risk locally advanced PSCC will have relapsed or refractory cancer after cisplatin-based combination chemotherapy. These patients have dismal outcomes with salvage chemotherapy, highlighting the major unmet need to expand our knowledge of the disease’s biology and develop clinical trials that use novel systemic agents. This narrative review synthesizes relevant publications retrieved from PubMed. Our aim is to discuss current approaches in the management of PSCC, summarize ongoing efforts to improve care, and identify future areas for enhancing our understanding of the disease.     

Everolimus in the treatment of renal cell carcinoma and neuroendocrine tumors

Renal cell carcinoma (RCC) and neuroendocrine tumors (NET) are uncommon malignancies, highly resistant to chemotherapy, that have emerged as attractive platforms for evaluating novel targeted regimens. Everolimus is an oral rapamycin derivative within the mammalian target of rapamycin class of agents. Preclinical series have shown that everolimus exhibits anticancer effects in RCC and NET cell lines. A phase 3 placebo-controlled study in advanced clear-cell RCC, known as RECORD-1 (for “REnal Cell cancer treatment with Oral RAD001 given Daily”), documented that everolimus stabilizes tumor progression, prolongs progression-free survival and has acceptable tolerability in patients previously treated with the multikinase inhibitors sunitinib and/or sorafenib. Everolimus has been granted regulatory approval for use in sunitinib-pretreated and/or sorafenib-pretreated advanced RCC and incorporated into clinical practice guidelines, and the RECORD-1 safety data are being used to develop recommendations for managing clinically important adverse events in everolimus-treated patients. Ongoing clinical trials are evaluating everolimus as earlier RCC therapy (first-line for advanced disease and as neoadjuvant therapy), in non-clear-cell tumors, and in combination with various other approved or investigational targeted therapies for RCC. Regarding advanced NET, recently published phase 2 data support the ability of everolimus to improve disease control in patients with advanced NET as monotherapy or in combination with somatostatin analogue therapy, octreotide long-acting release (LAR). Forthcoming data from phase 3 placebo-controlled trials of everolimus, one focused on monotherapy for pancreatic NET and the other on combination use with octreotide LAR for patients with advanced NET and a history of carcinoid syndrome, will provide insight into its future place in NET therapy. The results of a number of ongoing phase 3 evaluations of everolimus will determine its broader applicability in treating breast cancer (in combination with chemotherapy and hormonal therapy), several advanced gastrointestinal cancers, hepatocellular carcinoma, and lymphoma (in the adjuvant setting), as well as the various lesions associated with the tuberous sclerosis complex tumor suppressor gene.     

The impact of estrogen replacement therapy and raloxifene on osteoporosis, cardiovascular disease, and gynecologic cancers

OBJECTIVE: To compare the clinical utility of estrogen replacement therapy (ERT) and raloxifene in osteoporosis and cardiovascular disease in postmenopausal women and to evaluate the contrasting adverse effects of these therapies. DATA SOURCES: A MEDLINE search was performed for January 1980 through September 1998 using the key terms raloxifene, estrogen, CVD, lipoproteins, and osteoporosis. STUDY SELECTION AND DATA EXTRACTION: All clinical studies assessing ERT and raloxifene in cardiovascular disease or osteoporosis were evaluated. DATA SYNTHESIS: ERT remains the standard for prevention and treatment of osteoporosis in women. Its use increases total bone mineral density (BMD) up to 12.1% and reduces hip fracture risk by 66-73%. It reduces low-density lipoprotein (LDL) cholesterol by 15-19% and increases high-density lipoprotein (HDL) cholesterol by 6-18%. Raloxifene, an alternative to ERT in the prevention of osteoporosis, increases total BMD by 2.2%. It reduces LDL by 6.2-14.1% and increases HDL by 1.5-5.7%. Preliminary data suggest that raloxifene has contrasting effects on gynecologic cancers compared with the increased risk posed by ERT. CONCLUSIONS: Clinical trials have illustrated greater effects on BMD with ERT than with raloxifene. Studies of significant duration assessing raloxifene and its fracture risk effects are lacking. ERT appears to have greater beneficial cardiovascular risk factor effects than raloxifene. Prospective, primary prevention studies evaluating overall cardiovascular risk reduction do not exist for either intervention. Raloxifene, while more costly, is an alternative that may have a lower associated risk of breast cancer compared with ERT.