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El artículo presenta una inédita entrevista al Profesor Robert P. George (Universidad de Princeton, Estados Unidos) realizada con el fin de acercar a académicos procedentes de países no anglosajones, una visión panorámica de los principales temas que actualmente son objeto del debate jurídico y político desde una perspectiva no continental. Como se desarrolla en el texto, el ámbito anglosajón ha recuperado la desacreditada noción de derecho natural, a través de la Nueva Escuela del Derecho Natural. A través de esta nueva visión del derecho natural, Robert P George presenta una clara defensa de derechos e instituciones que actualmente se encuentran atacados por la tiranía de "lo políticamente correcto". George por medio la poderosa fuerza de la verdad y por medio de una clara y exquisita argumentación, invita a su interlocutor -sea en las aulas o a través de sus obras- a pensar por sí mismos sin miedo a poner en tela de juicio incluso las ideas y convicciones más profundas. Esto porque si como consecuencia del diálogo recibo luces nuevas que desconocía, puedo rectificar y se acercarme así a una verdad más plena. Si, por el contrario, recibo explicaciones poco fundamentadas o si el razonamiento adolece de fallos lógicos, me servirá para fortalecer las propias ideas, que deben presentarse siempre con la apertura de quien no se considerar infalible. Asimismo se analiza detenidamente la naturaleza del derecho natural, tal como lo entiende la Nueva Escuela de Derecho Natural, en cuya escuela se inscribe como uno de sus principales figuras. Presenta también las críticas de las que, con cierta frecuencia, esta nueva escuela es objeto. Resulta por ello un texto iluminador para juristas y filósofos interesados en conocer de primera mano los principios de la Nueva Escuela de Derecho Natural, aún poco difundida en la tradición continental. aspecto de gran interés es su exposición de la metodología que, a su entender, debe guiar la interpretación constitucional. Para juristas no interiorizados del todo en la tradición del Common Law anglosajón, resulta muy esclarecedora su explicación acerca del modo en que deben proceder los jueces en la resolución de los casos. Estos deben limitarse, indica Robert P George, al papel que la Constitución les ha atribuido: aplicar la ley, tal cual ésta es. De este modo, ante la frecuente tendencia a convertirse indirectamente en legisladores, alerta que ese modo de proceder supone violar la Constitución que han jurado defender. Un tema que se trata en extenso, es el del papel de la religión en la vida pública. Si bien nuestro autor prefiere utilizar argumentos de razón en su defensa de valores, se trate de la protección de la vida humana en todas sus instancias, del matrimonio como la unión de un varón y una mujer abierto a la vida, de la defensa de la libertad, etc. deja claro que la religión constituye una instancia con pleno derecho a participar aportando conocimientos y valores en favor del bien común socio-político, tal como lo han hecho muchas de las figuras más relevantes de la historia de los Estados Unidos. De este modo, no aboga por la neutralidad en el esfera pública, como tampoco apoya un gobierno sacro. Aboga, por una sociedad no sólo “civil” sino “civilizada”, es decir aquella en la que cada ciudadano puede manifestar con sus palabras y su conducta el propio modo de ver las cosas, en un ámbito de respeto mutuo que no se identifica con un relativismo. Sí se espera que cada ciudadano al presentar su ideas o conductas, sea capaz de dar razón de ellas, ya sea desde una perspectiva secular o religiosa. This article presents an unpublished interview with Professor Robert P. George (Princeton University, USA) with the aim of reaching out to scholars from non-Anglo-Saxon countries in order to offer a comprehensive view of the main issues currently being debated by legal and political scholars from a non-continental viewpoint. The text shows how a significant number of Anglo-Saxon scholars have recovered the discredited notion of natural law, through the so-called “New School of Natural Law”. With this new approach to natural law, George presents a clear defense of rights and institutions currently confronted by the tyranny of “the politically correct”. One powerful aspect of this new School includes the elaboration of arguments and counter-arguments to one’s own position. In this way, George invites his participant –whether in the classroom or through his dialectical works– to think for him or herself without fear of questioning even one’s deepest ideas and convictions. As a consequence of this thought process, one is able to receive new lights and, thus, rectify and reach a more complete truth. If, on the contrary, one has unsupported explanations or reasonings with logical fallacies, the method will strengthen one’s personal ideas, which must always be presented with the openness of those who do not consider themselves infallible. The main topic of this article is a detailed analysis of the natural law, as understood by the “New School of Natural Law”, in which George is inscribed as one of its main protagonists. It also presents the criticisms of which this New School is frequently the object. It should be therefore an enlightening text for jurists and philosophers interested in knowing first¬hand the principles of this School, still not widespread in the continental tradition. Another aspect of interest is the exposition of the methodology that, according to George, should guide Constitutional Interpretation. For jurists not fully internalized in the tradition of Anglo-Saxon Common Law, his explanation of how judges should proceed when resolving different cases is insightful. The judges must be limited, says George, to the role that the Constitution has assigned to them: to apply the law as is. Thus, Given the frequent tendency for judges to indirectly become legislators, he warns that this mode of proceeding presupposes frequent violations of the Constitution that they have sworn to defend. Another topic extensively argued is the role of religion in public life. Although George prefers to make use of rational arguments in his defense of values (among them the protection of human life in all its instances, marriage as the union of a man and a woman open to life, or the defense of freedom, etc.), he makes it clear that religion has the right to participate in public life by contributing its knowledge and values in favor of the socio-political common good as many important figures have done in the history of United States. Hence, George does not advocate neutrality in the public sphere, nor does he support the opposite extreme: a “sacred public square”. He supports a society that is not only “civil” but also “civilized”, that is to say, a society in which every citizen can manifest his words and/or his ideas and beliefs in an ambiance of mutual respect. Such a society believes that every citizen not only has the right to think, to believe and to live according to his views, but also is able to give reasons for them, whether from a secular or religious perspective.

Measurement of serum prostate-specific antigen (PSA) levels has revolutionised all aspects of the management of men with prostate cancer. As well as monitoring established disease, PSA testing has an important role in the early detection of prostate cancer. Although some men will undoubtedly benefit from early detection and treatment, concerns are raised by the poor specificity of the PSA test and the lack of conclusive evidence that early detection and treatment of prostate cancer carries survival benefits. As men become more aware of PSA testing through both the media and the Internet, clinicians are being placed under increasing pressure to carry it out. This review explores the arguments for and against PSA screening in asymptomatic men.

At present there are no effective treatment options for patients with hormone-refractory prostate cancer (HRPC) and current medical management is largely palliative. Therefore, there is a need for novel, non-cytotoxic treatment approaches in HRPC. Cancer development is a multistep process, involving initiation, proliferation, angiogenesis, invasion, and metastasis, each of which present potential targets for anticancer therapy. A number of agents exploiting each of these cellular targets are in clinical development and are reviewed in this article, particularly: inhibitors of the epidermal growth factor signalling cascade (e.g. cetuximab, trastuzumab, and ZD1839 [‘Iressa']); endothelin-A receptor antagonists (e.g. atrasentan); and angiogenesis inhibitors (e.g. ZD6474 and PTK 787). Other potential approaches include novel uses of existing compounds, inhibition of invasion/metastasis, induction of apoptosis, and gene therapy. These novel approaches and agents have the potential to be used in sequence or combination with established therapies, but also in combination with other new treatments. New, targeted biological therapies should lead to many more therapeutic options and better outcomes for patients with prostate cancer, particularly those with HRPC.

Stimulation of the signal transduction pathway of the epidermal growth-factor receptor (EGFR) tyrosine kinase family of receptors in tumor cells enhances cellular proliferation, prevents apoptosis, and promotes tumor-cell mobility, adhesion, and invasion. Therapeutic approaches used to target the EGFR and its signal transduction cascade include (1) monoclonal antibodies (eg, cetuximab [IMC-C225]) directed against the extracellular binding domain of the receptor; and (2) trastuzumab, a monoclonal antibody binding to the HER2 receptor; immunotoxin conjugates use an antibody directed against EGFR joined to a cell toxin. All are in clinical trials for a number of cancers, including prostate cancer. Antisense strategies are in preclinical development. Low-molecular-weight inhibitors of the EGFR tyrosine kinase also in clinical development include OSI-774, PD182905, PKI-166, CI-1033, and ZD1839. ZD1839 has shown encouraging results in patients with prostate cancer in phase 1 trials. mn

Objectives. To compare the efficacy, tolerability, and quality of life benefits of bicalutamide (Casodex) 150-mg/day monotherapy and castration in previously untreated nonmetastatic (MO) advanced prostate cancer. Methods. A total of 480 patients with Stage T3/T4 nonmetastatic disease randomly received oral bicalutamide 150 mg/day or castration (either bilateral orchiectomy or goserelin acetate [Zoladex] 3.6 mg every 28 days) in a 2:1 ratio in two open multicenter studies (studies 306 and 307). The design of these studies was similar to allow a pooled analysis. Results. In the combined survival analysis, at median follow-up of 202 and 205 weeks in studies 306 and 307, respectively, with 31% of the cases resulting in death, bicalutamide 150-mg monotherapy was statistically equivalent to castration; the risk of death from any cause was 7% less with bicalutamide than with castration (hazard ratio [HR] = 0.93). Data on time to treatment failure and objective progression could not be pooled, as results for these end points differed between the trials. In study 306, bicalutamide 150-mg monotherapy increased time to objective progression (HR = 0.58; P = 0.033) and treatment failure (HR = 0.66; P = 0.074), whereas in study 307, time to progression (HR = 1.35; P = 0.0471) and treatment failure (HR = 1.24; P = 0.097) favored castration. Bicalutamide therapy showed significant advantages over castration for both sexual interest (P = 0.029) and physical capacity (P = 0.046). Bicalutamide 150-mg monotherapy was well tolerated. Conclusions. Bicalutamide 150-mg monotherapy provides a similar survival outcome to castration in previously untreated patients with nonmetastatic advanced prostate cancer and confers statistically significant benefits over castration with respect to sexual interest and physical capacity.

BACKGROUND Bicalutamide (Casodex®) is a new nonsteroidal antiandrogen developed for use in patients with prostate cancer. The efficacy and tolerability of bicalutamide as monotherapy and as combination therapy for patients with advanced prostate cancer have been evaluated in randomized clinical trials. Clinical trials are currently in progress to further evaluate bicalutamide as monotherapy in patients with advanced stages of disease and as adjuvant or first-line therapy in patients with early-stage disease. METHODS A review of published trials of bicalutamide focusing on dose-ranging investigations, phase II and phase III monotherapy trials, a phase III trial of combined androgen blockade, and a safety overview. RESULTS In dose-ranging trials, bicalutamide doses of 10-200 elicited biochemical, objective, and subjective responses; higher bicalutamide doses (up to 600 mg) have also been evaluated. A 50-mg daily dose of bicalutamide was initially evaluated as monotherapy in phase II and phase III trials; in subsequent trials, a 150-mg daily dose was investigated. A 150-mg daily dose is considered to provide equivalent survival outcome compared with castration in patients with locally advanced prostate cancer, whereas the benefits of a better quality of life and better palliation with the 150-mg daily bicalutamide dose relative to castration in patients with metastatic disease needs to be balanced against the small shortfall (median difference, 42 days) in survival. In combination with a luteinizing hormone-releasing hormone agonist analogue (LHRH-A), a 50-mg daily dose of bicalutamide has equivalent efficacy to a corresponding flutamide (250 mg three times daily) combination regimen. Treatment with the bicalutamide combination regimen resulted in a longer median survival than with the flutamide combination regimen. Bicalutamide is well tolerated when used as monotherapy or in combination with a LHRH-A. The benefits of bicalutamide as monotherapy include retention of libido and sexual potency and as combination therapy a lower incidence of diarrhea relative to flutamide. CONCLUSIONS A 50-mg daily dose of bicalutamide is sufficient when given in combination with an agent, such as a LHRH-A, that lowers serum testosterone, but higher doses of bicalutamide may be needed when the drug is given as monotherapy. Bicalutamide, 50-mg daily, is a logical first choice for antiandrogen therapy when used in combination with an LHRH-A for the treatment of patients with advanced prostate cancer. Bicalutamide 150-mg daily is considered an effective monotherapy for use in patients with locally advanced disease. Additional clinical trials are currently in progress to further evaluate bicalutamide as a monotherapy for advanced prostate cancer and to assess its value as adjuvant or first-line therapy for early-stage prostate cancer. Prostate 34:61–72, 1998. © 1998 Wiley-Liss, Inc.

To evaluate bicalutamide as a therapy in nearly 3000 patients with advanced prostate cancer and to determine the dose-ranging, pharmacodynamic, and pharmacokinetic properties of bicalutamide. To evaluate bicalutamide as a monotherapy or in combination with luteinizing hormone-releasing hormone analogue (LHRH-A) therapy.Bicalutamide is a potent, nonsteroidal antiandrogen with a plasma half-life consistent with a once-daily schedule. Monotherapy trials with 50 mg of bicalutamide established its intrinsic activity, as demonstrated by subjective and objective responses and decreases in PSA concentrations. In comparison with castration, 50 mg of bicalutamide monotherapy was inferior with respect to survival. In a randomized, double-blind (for antiandrogen therapy) trial, with a median follow-up of 49 weeks, 50 mg of bicalutamide plus an LHRH-A was superior (P = 0.005) to flutamide plus an LHRH-A in delaying time-to-treatment failure and was better tolerated, as was evident from a significantly (P0.001) lower incidence of diarrhea and fewer withdrawals for adverse events among bicalutamide-treated patients. With longer follow-up and a 34% mortality, survival was equivalent between groups. Dose-related effects of bicalutamide on serum PSA concentrations were clearly demonstrated in the clinical trial program. With a total exposure of2800 patient-years, bicalutamide has been shown to be a well-tolerated therapy with a low incidence of treatment-related withdrawals.Bicalutamide is a new antiandrogen that offers the convenience of once-daily administration, demonstrated activity in prostate cancer, and an excellent safety profile. Because it is effective and offers better tolerability than flutamide, bicalutamide represents a valid first choice for antiandrogen therapy in combination with castration for the treatment of patients with advanced prostate cancer.

Maximum androgen blockade, a relatively recent development in the treatment of prostate cancer, combines medical or surgical castration with antiandrogen therapy. A large randomized study comparing the non-steroidal antiandrogen, bicalutamide, with flutamide, each in combination with luteinizing hormone-releasing hormone (LHRH) analogs, showed that after a median follow-up of 49 weeks, the time to treatment failure was significantly longer for the bicalutamide patients compared with the flutamide patients (p = 0.005). After a median follow up to 95 weeks, bicalutamide in combination with LHRH analog therapy produced at least equivalent efficacy with flutamide in combination with LHRH analog therapy in terms of time to treatment failure and equivalent efficacy in terms of survival. The tolerability profile of bicalutamide, as based on reported findings and a literature review, indicates a superior tolerability to that of currently available antiandrogens, particularly with respect to diarrhea with a low incidence of treatment-related withdrawals.

The number of new agents being developed for the treatment of cancer has, over the past 10 years, increased dramatically which has resulted in increased interactions between the pharmaceutical industry that discover and develop most new agents and investigators in academic institutions, hospitals and office practices. This close interaction has inevitably led to a number of issues being identified on both sides and this paper will attempt to identify some of these and propose solutions.

The development of effective, novel, targeted cancer therapies with minimal side effects has long been a goal in cancer research. A key group of targets identified for drug development consists of the receptor tyrosine kinases, which have pivotal roles in the growth factor signaling that is subverted in carcinogenesis and in the host processes, such as angiogenesis, involved in tumor progression.A literature review of the role of receptor tyrosine kinases in human malignancies is followed by a discussion of the potential use of inhibitors of receptor tyrosine kinases as anticancer therapy, focusing on the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (Iressa, ZD1839, AstraZeneca, Macclesfield, United Kingdom).Several small molecule inhibitors that are specific to individual receptor tyrosine kinases have been developed and a number of these potential anticancer agents are progressing through clinical trials. Various surrogate end points are being assessed to demonstrate the activity of these inhibitors against their targets. Results from studies of gefitinib alone and with the antiandrogen bicalutamide in both hormone dependent and independent prostate tumor xenografts suggested that gefitinib may have potential as monotherapy and combination therapy in the treatment of both forms of the disease. Gefitinib is currently undergoing further preclinical and clinical evaluation for the treatment of prostate cancer.A number of tyrosine kinase inhibitors, including gefitinib, are progressing through clinical development and are beginning to provide new treatment options for a range of malignancies.

Objectives. Bicalutamide is a nonsteroidal competitive inhibitor of androgens at the androgen receptor. The level of blockade that can be achieved is dependent on the relative numbers of molecules of the agonist and of the competitive antagonist around the receptor. Increasing the dose of a competitive inhibitor, therefore, should potentially increase the level of blockade. Bicalutamide has been investigated extensively at daily doses up to 150 mg, and there is evidence of increasing blockade at doses up to this point, as evidenced by increasing suppression of prostate-specific antigen (PSA) and also improvement in response rate, both subjective and objective. At doses of up to 150 mg, increases in plasma concentration of bicalutamide were approximately linear, and all doses were equally well tolerated. It was thought, therefore, that there was a case for investigating higher doses of bicalutamide to determine whether increased androgen blockade could be achieved with the use of bicalutamide as monotherapy. Methods. A number of studies have now been carried out evaluating bicalutamide in daily doses of 200 mg, 300 mg, and 450 mg. The 200-mg dose has been evaluated as a primary treatment for advanced prostate cancer and also as a second-line treatment option for patients who have demonstrated a flutamide withdrawal response. Results. In noncomparative trials, the decline in PSA value associated with daily doses of 200 mg bicalutamide was greater than that observed with daily doses of 150 mg, and there was also a slightly higher response rate. When 200 mg daily doses were used as therapy following failure of flutamide in combination with castration, and also following evidence of a flutamide withdrawal response, further responses were seen, perhaps suggesting the theory that in some prostate cancer cell mutations, bicalutamide acts as a pure antagonist rather than as a partial agonist. More recently, bicalutamide has been evaluated at higher doses: 20 patients have been exposed for periods up to 6 months at daily doses of 300 mg. This dose was well tolerated, and evidence of PSA suppression and responses were seen that were at least equivalent to those observed at lower doses. Pharmacokinetics evaluation has been carried out at this dose, and there is now evidence of nonlinearity of plasma concentrations, suggesting that further dose escalation is unlikely to confer major additional benefit over the 150- and 200-mg doses. To confirm the evidence of nonlinearity of plasma concentrations at doses >200 mg, a randomization between 450 mg bicalutamide and medical castration is currently being carried out. Patients are still being recruited into this trial, but there has been no evidence of any change in the tolerability profile of bicalutamide at any dose >150 mg. Conclusions. In summary, bicalutamide has shown increasing evidence of activity as a competitive blocker of the androgen receptor at daily doses of up to 200 mg. At daily doses >200 mg, there is evidence of nonlinearity of plasma concentrations, and therefore further benefit is unlikely to be seen as a result of further escalating the dose of bicalutamide.