An update on prostate cancer research

The pathogenesis of prostate cancer reflects complex interactions among environmental and genetic factors. Recent advances suggest molecular mechanisms that may explain geographic and ethnic variations in prostate cancer incidence, and understanding of molecular disease progression is advancing rapidly. Clinically, the case for screening has become stronger, and declining prostate cancer mortality rates may be due in part to early detection and treatment. Improved risk assessment for patients with localized disease is now available, although further refinement in predictive algorithms will need to incorporate validated molecular prognostic markers. Treatment options for patients with localized prostate cancer have expanded and the role of androgen deprivation further delineated. Finally, treatment strategies for patients with androgen-independent disease have also expanded, although novel therapies are required to improve survival in this group of patients.     

Neoadjuvant and adjuvant chemotherapy for high-risk localized prostate cancer

Opinion statement The optimal treatment strategy for patients with high-risk localized prostate cancer remains unknown. Definitive local treatments such as radical prostatectomy and external beam radiotherapy cure only a minority of these patients. Recent efforts have been made to reduce the risk of recurrence and delay progression to symptomatic hormone-refractory disease by using chemotherapy before, during, or after definitive local therapy. Chemotherapy is an effective modality in the treatment of hormone-refractory prostate cancer. Studies have established its role in the palliation of symp-toms in patients with hormone-refractory disease, though a survival benefit remains to be demonstrated. Prospective randomized trials are underway to test the hypothesis that neoadjuvant and adjuvant chemotherapy may improve survival rate in patients with high-risk localized prostate cancer. The data currently available from nonrandom-ized trials have not yet established the exact role of neoadjuvant and adjuvant che-motherapy and its potential impact on survival. However, preliminary data suggest that chemotherapy, when administered in concert with definitive local therapy, may be promising in patients with locally advanced prostate cancer. Randomized clinical trials are ongoing to see if neoadjuvant and adjuvant chemotherapy will translate into an improved clinical benefit for the patient, and participation by patients is para-mount. We review the recent literature regarding the use of neoadjuvant and adjuvant chemotherapy in patients with locally advanced prostate cancer.     

Evolving role of surgery, radiation, hormone therapy, and chemotherapy in high-risk locally advanced prostate cancer

Locally advanced prostate cancer encompasses several disease states that vary in the risk for progression and recurrence after Initials treatment. Further, the optimal treatment strategies for locally advanced prostate cancer are continuing to evolve, reflecting the complex nature of this disease state. For many patients, clinical experience demonstrates that a combined approach of locally directed therapy and systemic therapy is likely to provide better long-term outcome than singlemodality therapy. Randomized studies have established hormone ablation with external-beam radiation as an important form of treatment for this group of patients. However, additional progress needs to be made, particularly in the subgroup of patients with very high-risk disease features. As the optimal integration of local and systemic treatments becomes more clearly defined, the long-term prognosis for patients with high-risk locally advanced prostate cancer will improve.     

Evolving Role of Surgery,Radiation, Hormone Therapy,and Chemotherapy in High-Risk Locally Advanced Prostate Cancer

Locally advanced prostate cancer encompasses several disease states that vary in the risk for progression and recurrence after Initials treatment. Further, the optimal treatment strategies for locally advanced prostate cancer are continuing to evolve, reflecting the complex nature of this disease state. For many patients, clinical experience demonstrates that a combined approach of locally directed therapy and systemic therapy is likely to provide better long-term outcome than singlemodality therapy. Randomized studies have established hormone ablation with external-beam radiation as an important form of treatment for this group of patients. However, additional progress needs to be made, particularly in the subgroup of patients with very high-risk disease features. As the optimal integration of local and systemic treatments becomes more clearly defined, the long-term prognosis for patients with high-risk locally advanced prostate cancer will improve.     

Surgical and medical treatment for localized prostate cancer

With the advent of prostate-specific antigen (PSA) screening, prostate cancer is increasingly diagnosed in the early stage. For localized prostate cancer, radical prostatectomy is considered the most reliable curative therapy. Radiation therapy can also be curative in localized prostate cancer. Watchful waiting is a reasonable approach in adequately selected cases. More recently, several investigations reported the usefulness of primary hormone therapy for localized and locally advanced prostate cancer, especially for patients showing a favorable initial response. This article summarizes briefly reviews of various approaches in localized prostate cancer.     

Prospects of immunotherapy for the treatment of prostate carcinoma--a review.

The treatment of prostate carcinoma is dependent on the stage of the disease. Patients who present with clinically localized cancer or locally advanced tumors can be potentially cured by radical prostatectomy, radiation, and hormonal therapy. However, disease progression can occur in 30-50% of patients diagnosed with clinically localized cancer. The bone is the predominant site of metastases. Metastatic prostate cancer is first treated by androgen blockade but within a few months becomes hormone refractory. Hormone refractory metastatic prostate cancer is not responsive to conventional treatments, and patients have an expected survival of less than a year. It is essential to develop new approaches for the treatment of hormone refractory metastatic disease. Immunotherapy, based on enhancement of the host immune response against the tumor, has been used as an alternative therapy for the treatment of metastatic cancers refractory to conventional therapy in particular for melanoma and renal cell carcinoma. In this review, we will summarize various immunotherapeutic approaches developed over the last 18 years, and we will address the potential of immunotherapy for the treatment of metastatic prostate carcinoma by reviewing preclinical studies and initial clinical trials performed in this field.     

Height-related risk factors for prostate cancer

Previous studies have reported that adult height is positively associated with the risk of prostate cancer. The authors carried out a population-based case-control study involving 317 prostate cancer cases and 480 controls to further investigate the possibility that height is more strongly associated with advanced, compared with localized forms of this disease. Since the inherited endocrine factors, which in part determine height attained during the growing years, may influence the risk of familial prostate cancer later in life, the relationship with height was also investigated for familial versus sporadic prostate cancers. Adult height was not related to the risk of localized prostate cancer, but there was a moderate positive association between increasing height and the risk of advanced cancer (relative risk (RR) = 1.62; 95% confidence interval (CI) 0.97-2.73, upper versus lowest quartile, P-trend = 0.07). Height was more strongly associated with the risk of prostate cancer in men with a positive family history compared with those reporting a negative family history. The RR of advanced prostate cancer for men in the upper height quartile with a positive family history was 7.41 (95% CI 1.68-32.67, P-trend = 0.02) compared with a reference group comprised of men in the shortest height quartile with a negative family history. Serum insulin-like growth factor-1 levels did not correlate with height amongst men with familial or sporadic prostate cancers. These findings provide evidence for the existence of growth-related risk factors for prostate cancer, particularly for advanced and familial forms of this disease. The possible existence of inherited mechanisms affecting both somatic and tumour growth deserves further investigation.     

Intraoperative Radiation Therapy for Locally Advanced or Locally Recurrent Rectal Cancer

Colorectal cancer is a major cause of morbidity and mortality across the world. Although surgery alone is very effective for patients with early stage disease, patients with more advanced disease required a combined modality approach. Standard doses of radiation therapy are usually ineffective in controlling localized disease that cannot be widely resected. Radiation dose escalation with intraoperative radiation therapy (IORT) has been investigated for many years as a component of a trimodality strategy in patients at high risk for local recurrence. This paper reviews the evidence supporting inclusion of IORT in addition to external beam radiation, surgery, and chemotherapy in patients with very locally advanced primary rectal cancer and patients with locally advanced recurrent rectal cancer.     

Neoadjuvant therapy for high-risk localized prostate cancer

Prostate cancer patients with clinical stage T3 disease, biopsy Gleason scores of 8 to 10, or serum prostate-specific antigen levels greater than 20 ng/mL are at high risk of recurrence despite local therapy. Although hormonal therapy has palliative benefit for the majority of patients with metastatic disease, randomized trials have not demonstrated a survival benefit for its administration prior to surgery for locally advanced disease. Historically, chemotherapy has been felt to have little activity in hormone-refractory prostate cancer, but new evidence may refute this belief. Ongoing clinical trials are now investigating the use of chemotherapy in the neoadjuvant setting. We review the recent literature regarding the use of neoadjuvant hormonal manipulation, chemotherapy, and promising new molecular targeted agents in patients with high-risk localized prostate cancer.     

Radiation therapy combined with hormone therapy for prostate cancer

Standard-dose radiation therapy has limited capacity to cure bulky and locally advanced prostate cancer. Multiple randomized trials have shown a clinical benefit to adding androgen suppression therapy to external-beam radiation therapy in several subsets of prostate cancer. These studies have made combining hormonal therapy with radiation therapy the standard of care for men with locally advanced (T3-4) and unfavorable prostate cancers (Gleason score >or=8 and/or prostate-specific antigen >20 ng/mL). The clinical impact of hormonal therapy has been seen in biochemical control, local control, distant metastases, disease-specific survival, and overall survival. If hormonal therapy is to be combined with radiation, it should be initiated before the start of radiation and continued during the radiation course rather than used only in the adjuvant setting. Typically, shorter-term hormone therapy is defined as regimens of 4 to 6 months, with longer-term hormone therapy describing durations beyond 24 months. Historically, longer-term hormone therapy was thought to have a more profound systemic effect; however, with the emerging use of hormonal therapy for less-advanced disease, the overall impact of shorter-course hormone therapy is being seen. This review will summarize trials using hormonal therapy and radiation with an emphasis on phase III studies and describe the more recent integration of hormone therapy with radiation for prostate cancer.     

Alcohol and smoking and subsequent risk of prostate cancer in Japanese men: The Japan Public Health Center‐based prospective study

Although alcohol and smoking have not been established as risk factors for prostate cancer, they are important risk factors for other human cancers and potentially major avoidable factors. Alcohol drinkers and smokers might be less likely to get screening, which might lead to attenuation of the positive association. Here, we investigated the association of alcohol drinking and smoking and prostate cancer according to stage, as well as prostate cancer detected by subjective symptoms, in a large prospective study among Japanese men. The Japan Public Health Center‐based prospective study (JPHC study) was established in 1990 for Cohort I and in 1993 for Cohort II. Subjects were 48,218 men aged 40–69 years who completed a questionnaire, which included their alcohol and smoking habits at baseline, and who were followed until the end of 2010. During 16 years of follow‐up, 913 men were newly diagnosed with prostate cancer; of whom 248 had advanced cases, 635 were organ‐localized and 30 were of an undetermined stage. Alcohol consumption was dose‐dependently associated with advanced prostate cancer [nondrinkers: reference, 0–150 g/week: hazard ratio (HR) = 1.23, 95% confidence interval (CI) = 0.83–1.82; 150–300 g/week: HR = 1.51, 95% CI = 1.04–2.19; ≥300 g/week: HR = 1.41, 95% CI = 0.97–2.05, p for trend = 0.02]. The positive association was not substantially changed among cancers detected by subjective symptoms. Smoking was inversely associated with prostate cancer among total subjects, but tended to increase the risk of advanced prostate cancer detected by subjective symptoms. In conclusion, abstinence from alcohol and prohibition of smoking might be important factors in the prevention of advanced prostate cancer.     

Stem Cell Genes in Androgen-independent Prostate Cancer

Despite recent advances in the detection and treatment of early stage prostate cancer, there remains little effective therapy for patients with locally advanced and/or metastatic disease. Although the majority of patients with advanced disease respond initially to androgen ablation therapy, most go on to develop androgen-independent tumors that are inevitably fatal. Therefore, understanding the mechanisms by which a hormone-sensitive tumor escapes hormonal control is critical to the development of effective therapeutic modalities. The study of the differentiation pathways of normal and abnormal prostate growth has led to the development of a stem cell model for prostate cancer [1–3]. Recent work discussed in this commentary suggests that prostate tumors resist apoptosis and proliferate by adopting features of normal prostatic stem/progenitor cells. Basal cells, the putative stem/progenitor cells of the prostate, possess the phenotype of androgen-independence as do most advanced prostate cancers. Therefore, the study of basal cells may prove critical to understanding prostate carcinogenesis and to the development of novel strategies for preventing and managing prostate cancer.     

Treatment strategy for elderly patients with prostate cancer

Because of both the indolent and aggressive nature of prostate cancers, it is not easy to select the best treatment for elderly patients with a high prevalence of comorbidities. Since the growth of prostate cancer is generally slow and all treatments adversely affect the quality of life to some degree, conservative treatment may well be the best option for elderly patients with prostate cancer. In fact, previous studies have indicated that the rate of prostate cancer death was not high in patients with low-intermediate risk of prostate cancer who were treated conservatively. However, it is also true that we often encounter elder patients with a locally advanced cancer who had not been exposed to PSA screening. Previous reports also support aggressive treatment such as hormonal therapy, external radiation and brachytherapy alone or in combination for healthy elderly men with high-risk prostate cancer. Thus, after a careful evaluation of the nature of the cancer and comorbidity, we found that both conservative and aggressive treatments are applicable for elderly patients with prostate cancer to maintain their quality of life.     

Current trends for the use of androgen deprivation therapy in conjunction with radiotherapy for patients with unfavorable intermediate‐risk,high‐risk,localized, and locally advanced prostate cancer

Androgen deprivation therapy (ADT) is now a well‐established standard of care in combination with definitive radiotherapy for patients with unfavorable intermediate‐risk to high‐risk locally advanced prostate cancer. It is also well established that combination modality treatment with ADT and radiotherapy is superior to either of these modalities alone for the treatment of patients with high‐risk locally advanced disease. Current treatment guidelines for prostate cancer in the United States are based on the estimated risk of recurrence and death. This review examines the clinical evidence underpinning the use of ADT and radiotherapy among patients with high‐risk localized and locally advanced disease in the United States. This review also considers the rationale for moving from traditional luteinizing hormone‐releasing hormone agonists to more recently developed gonadotrophin‐releasing hormone antagonists. Cancer 2014;120:1620–1629 . © 2014 American Cancer Society.     

The Early Prostate Cancer program: bicalutamide in nonmetastatic prostate cancer

The Early Prostate Cancer program is investigating the addition of bicalutamide 150 mg to standard care for localized or locally advanced, nonmetastatic prostate cancer. The third program analysis, at 7.4 years' median follow-up, has shown that bicalutamide 150 mg does not benefit patients with localized disease, but does confer significant progression-free survival benefits in patients with locally advanced disease, irrespective of standard care received. In patients receiving radiotherapy for locally advanced disease, bicalutamide 150 mg significantly reduced the risk of death by 35%; the magnitude of this benefit compares favorably with that of adjuvant luteinizing hormone-releasing hormone agonist therapy in a similar population. Bicalutamide 150 mg represents an alternative to castration for patients with locally advanced disease who wish to avoid the side effects associated with castration.     

An evaluation of bicalutamide in the treatment of prostate cancer

Although prostate cancer is traditionally considered a disease of old age, improved diagnostic techniques have resulted in early diagnosis, and many men are now treated while still physically and sexually active. Current therapies for prostate cancer often include medical or surgical castration, which cause adverse effects on physical and sexual function; therefore, greater attention has been focused on quality of life. The nonsteroidal antiandrogen bicalutamide is an effective agent with a favorable tolerability profile and, in some settings, represents an alternative to castration. Mature survival data reveal that bicalutamide monotherapy provides survival benefits for untreated locally advanced disease that do not differ significantly from those of castration and maintains better physical capacity and sexual interest. Recent data from a prospective randomized trial demonstrate that bicalutamide given as immediate therapy, either alone or as adjuvant to therapy of curative intent, significantly reduces the risk of objective disease progression in patients with localized or locally advanced prostate cancer. Antiandrogens are also used in combination with castration, a treatment known as combined androgen blockade (CAB), for advanced disease. A randomized trial demonstrated that CAB with bicalutamide is associated with similar survival outcome to CAB with flutamide and is better tolerated. Current evidence demonstrates that bicalutamide currently has a favorable risk-benefit ratio in several stages of prostate cancer and that the role of bicalutamide will be further defined by ongoing studies.     

Familial prostate cancer

Prostate cancer is the most commonly diagnosed cancer among men in the United States as well as most Western countries. A significant proportion of men report having a positive family history of prostate cancer in a first-degree relative (father, brother, son), which is important in that family history is one of the only established risk factors for the disease and plays a role in decision-making for prostate cancer screening. Familial aggregation of prostate cancer is considered a surrogate marker of genetic susceptibility to developing the disease, but shared environment cannot be excluded as an explanation for clustering of cases among family members. Prostate cancer is both a clinically and genetically heterogeneous disease with inherited factors predicted to account for 40%–50% of cases, comprised of both rare highly to moderately penetrant gene variants, as well as common genetic variants of low penetrance. Most notably, HOXB13 and BRCA2 mutations have been consistently shown to increase prostate cancer risk, and are more commonly observed among patients diagnosed with early-onset disease. A recurrent mutation in HOXB13 has been shown to predispose to hereditary prostate cancer (HPC), and BRCA2 mutations to hereditary breast and ovarian cancer (HBOC). Genome-wide association studies (GWAS) have also identified approximately 100 loci that associate with modest (odds ratios <2.0) increases in prostate cancer risk, only some of which have been replicated in subsequent studies. Despite these efforts, genetic testing in prostate cancer lags behind other common tumors like breast and colorectal cancer. To date, National Comprehensive Cancer Network (NCCN) guidelines have highly selective criteria for BRCA1/2 testing for men with prostate cancer based on personal history and/or specific family cancer history. Tumor sequencing is also leading to the identification of germline mutations in prostate cancer patients, informing the scope of inheritance. Advances in genetic testing for inherited and familial prostate cancer (FPC) are needed to inform personalized cancer risk screening and treatment approaches.     

Treatment of locally advanced prostate cancer: is chemotherapy the next step?

PURPOSE: Management of locally advanced prostate cancer remains controversial. Various single and combination modality approaches have been advocated, but an accepted standard of care remains undefined. The purpose of this review is to define the current knowledge in managing locally advanced prostate cancer and to propose new treatment approaches based on current knowledge. MATERIALS AND METHODS: A MEDLINE search to detect all relevant articles on the management of locally advanced prostate cancer was performed. A review of the staging, natural history, and prognosis of this disease was also performed. RESULTS: The lack of a clearly defined treatment approach to patients with locally advanced prostate cancer stems from multiple factors, including ambiguities in clinical staging, inadequate knowledge of the natural history of the cancer, and a dearth of comparative randomized trials evaluating efficacy of different therapies. Single modality treatment, including radical prostatectomy (RP) or external-beam radiotherapy alone, is associated with high rates of failure. The use of adjuvant hormonal ablation therapy in combination with external-beam radiotherapy has shown improvement in progression-free and overall survival, although similar improvements have not been clearly demonstrated for surgical patients treated with hormonal therapy. New advances in chemotherapy for hormone-refractory prostate cancer suggest that response rates may be as high as 50% or more, and current trials are evaluating the addition of chemotherapy to hormonal ablation in either surgery or radiation therapy in locally advanced prostate cancer. CONCLUSION: Optimal management of locally advanced prostate cancer remains undefined. Standard treatment options include RP, external-beam radiotherapy, or hormonal ablation therapy, alone or in combination. New approaches being tested include improved methods for delivering radiation or combining hormonal ablation with surgery or radiation. It is possible that other forms of systemic therapy, including chemotherapy, may become important components of multimodality treatment. Clinical trials designed to test this hypothesis are ongoing.     

Keyrole of endocrinology in the victory against prostate cancer

The most significant discovery of the last quarter of the XXth century in the field of prostate cancer is probably the observation that the human prostate synthesizes locally an amount of androgens from the inactive steroid precursors dehydroepiandrosterone (DHEA) and its sulfate DHEA-S that is approximately equivalent to the androgens made in the testis. Based upon this observation, two important discoveries also made by our group are applied worlwide, namely the use of GnRH (gonadotropin -releasing hormone) agonists that completely block testicular androgen secretion, while, simultaneously, the androgens made locally in the prostate from DHEA are blocked in their access to the androgen receptor by a pure antiandrogen (flutamide, bicalutamide or nilutamide). This treatment, called combined androgen blockade, has been the first treatment demonstrated to prolong life in prostate cancer in prospective and randomized studies. While the first studies were performed in patients with advanced and metastatic disease, our recent data indicate a much higher efficacy of the same treatment applied to localized prostate cancer, thus leading to an at least 90 % possibility of cure. In fact, the lifesaving benefits of androgen blockade in prostate cancer have been largely underestimated. When compared to other cancer therapies, the results obtained are quite remarkable. A recent metaanalysis of all clinical trial data mostly gives the credit to follow-up hormone therapy. "Hormonal treatment as a whole works ridiculously well", as reported by Arnst. In fact, while death rates decreased by 1.1 % per year from 1993 to 2001 for all cancers combined, prostate cancer showed a larger decrease at 3.6 %. Although improvements in surgery and radiotherapy are likely to play a role, a study by Frank R. Lichtenberg using National Cancer Institute data obtained from 2.1 million cancer patients, has concluded that "cancer-fighting drugs improved survival rates, especially for cancer of the prostate, where drug innovations have been the greatest". The knowledge about the absence of development of resistance to androgen blockade in localized prostate cancer is extremely important. In fact, it is often erroneously believed that androgen blockade should not be administered early because resistance to treatment will develop and one might as well wait to use androgen blockade at a later stage of the disease. In fact, deferring treatment implies that, very often, it will then be too late, because after the cancer has migrated to the bones, resistance to treatment can no more be avoided. It should be realized that when prostate cancer is first detected, even by screening, the cancer is not small since its diameter is of the order of 1 cm or more. This is the most appropriate time to treat with the strong hope of a cure. With the presently available techniques, screening can diagnose prostate cancer at a clinically localized stage in 99 % of cases. Such an early diagnosis permits immediate treatment with a curative intent, combined androgen blockade (CAB) being a truly efficient alternative especially in older patients. Most importantly, CAB must be used immediately in patients who fail radical prostatectomy, radiotherapy of brachytherapy. When androgen blockade is used, it should always be combined androgen blockade. Using this strategy, based upon today's available diagnostic and therapeutic approaches, death from prostate cancer can be an exception, confirming that victory against prostate cancer is achieved.     

Risk factors for prostate cancer incidence and progression in the health professionals follow-up study

Risk factors for prostate cancer could differ for various sub-groups, such as for "aggressive" and "non-aggressive" cancers or by grade or stage. Determinants of mortality could differ from those for incidence. Using data from the Health Professionals Follow-Up Study, we re-examined 10 factors (cigarette smoking history, physical activity, BMI, family history of prostate cancer, race, height, total energy consumption, and intakes of calcium, tomato sauce and alpha-linolenic acid) using multivariable Cox regression in relation to multiple subcategories for prostate cancer risk. These were factors that we previously found to be predictors of prostate cancer incidence or advanced prostate cancer in this cohort, and that have some support in the literature. In this analysis, only 4 factors had a clear statistically significant association with overall incident prostate cancer: African-American race, positive family history, higher tomato sauce intake (inversely) and alpha-linolenic acid intake. In contrast, for fatal prostate cancer, recent smoking history, taller height, higher BMI, family history, and high intakes of total energy, calcium and alpha-linolenic acid were associated with a statistically significant increased risk. Higher vigorous physical activity level was associated with lower risk. In relation to these risk factors, advanced stage at diagnosis was a good surrogate for fatal prostate cancer, but high-grade (Gleason >/= 7 or Gleason >/= 8) was not. Only for high calcium intake was there a close correspondence for associations among high-grade cancer, advanced and fatal prostate cancer. Tomato sauce (inversely) and alpha-linolenic acid (positively) intakes were strong predictors of advanced cancer among those with low-grade cancers at diagnosis. Although the proportion of advanced stage cancers was much lower after PSA screening began, risk factors for advanced stage prostate cancers were similar in the pre-PSA and PSA era. The complexity of the clinical and pathologic manifestations of prostate cancer must be considered in the design and interpretation of studies.