Hormonal Maneuvers Research Articles

Mucinous Adenocarcinoma of the Prostate Found Incidentally in Adenomectomy Specimen Complicated with Vesicocutaneous Fistulae

Primary mucinous tumors of the prostate gland are rare, including mucinous adenocarcinoma, prostatic adenocarcinoma with mucinous features, and mucinous adenocarcinoma of the prostatic urethra. In this report, we present a case of a locally advanced mucinous variant of prostatic ductal adenocarcinoma, found incidentally during pathology examination of an adenomectomy specimen, after bladder outlet obstruction surgery. Recent large studies indicated that mucinous adenocarcinoma of the prostate, treated by radical prostatectomy, is not more aggressive than ordinary nonmucinous prostatic adenocarcinoma. In our case, the rapid deterioration of our patient, the return of tumor in its initial size soon after surgery, in addition to its distal metastatic spread should be attributed not only to the mucinous variant of prostatic adenocarcinoma but also to the advanced stage during initial diagnosis and the noncompliance of the patient with the suggested treatment after surgery, omitting radiotherapy, and hormonal maneuvers.

Abstract 4962: Very-small-nuclear circulating tumor cell (vsnCTC) as a putative biomarker for visceral metastasis in metastatic castration-resistant prostate cancer (mCRPC)

Abstract Introduction and Objective: Patients with metastatic castration-resistant prostate cancer (mCRPC) who develop visceral metastases (VM) have poorer clinical outcomes in comparison to those without VM. Currently, VM are discovered late in the clinical course of mCRPC-VM and this aggressive natural history typically culminates in organ failure. There are no existing tests that identify men at risk for VM other than radiography. Our team performed circulating tumor cell (CTC) enumeration using NanoVelcro CTC Assay on prostate cancer patients across the spectrum of metastatic states: no metastasis, non-visceral metastasis, and VM. We identified an association between the presence of very-small-nuclear CTCs (vsnCTCs, DAPI+/Cytokeratin+/CD45- with nuclear size < 8.5μm) and VM. Serial enumeration studies suggested the emergence of vsnCTCs occurred before the radiographic detection of VM, and the change of vsnCTC counts reflected the patients’ disease progression. We then hypothesized that presence of vsnCTC signals the presence of VM and has predictive and prognostic value with respect to VM. Methods: We identified mCRPC patients who had progressed through next generation hormonal maneuvers such as abiraterone, enzalutamide, or an equivalent drug. Serial blood specimens were used for vsnCTC enumeration using NanoVelcro CTC Assay as previously published. The vsnCTC counts were related to the presence and development of VM (evaluated by radiography) as well as the response to anti-cancer treatment. Results: Blood specimens were identified from 28 patients who met the eligibility criteria; 15/28 patients presented with VM and 13/28 had bone-only disease at their first CTC enumeration. Five out of 13 non-VM patients developed VM during follow-up, and vsnCTCs were detected 86-196 days prior to radiographic detection of VM (true positive); 4/13 had vsnCTCs detected but no VM was found by the time of analysis (false positive). None of the vsnCTC(-) patients developed VM. vsnCTCs were detected in 20/20 VM patients compared to 4/8 non-VM patients. Reduction of vsnCTC count occurred at initiation of anti-cancer treatment; transition from vsnCTC(-) to vsnCTC(+) was seen prior to progression under the treatment. Of the patients who have VM, 14 passed away at the time of this abstract submission including all the patients converting from non-VM to VM during the time of follow-up. Two out of 8 non-VM patients passed away including one patient who had vsnCTCs detected around 6 months prior to death. Conclusions: vsnCTCs are associated with the presence of VM. The vsnCTC is a potential biomarker for predicting the development of VM and monitoring the treatment response in mCRPC. Transition from vsnCTC(-) to vsnCTC(+) was associated with the development of VM and progression under the treatment. Citation Format: Jie-Fu Chen, Hao Ho, Elisabeth Hodara, Alexander Ureno, Ann Go, Elizabeth Kaufman, Margarit Sievert, Daniel J. Luthringer, Jiaoti Huang, Leland Chung, Zunfu Ke, Ker-Chau Li, Hsian-Rong Tseng, Edwin M. Posadas. Very-small-nuclear circulating tumor cell (vsnCTC) as a putative biomarker for visceral metastasis in metastatic castration-resistant prostate cancer (mCRPC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4962.

MP07-06 VERY-SMALL-NUCLEAR CIRCULATING TUMOR CELL (VSNCTC) AS A PUTATIVE BIOMARKER FOR VISCERAL METASTASIS IN METASTATIC CASTRATION-RESISTANT PROSTATE CANCER (MCRPC)

You have accessJournal of UrologyProstate Cancer: Markers II1 Apr 2016MP07-06 VERY-SMALL-NUCLEAR CIRCULATING TUMOR CELL (VSNCTC) AS A PUTATIVE BIOMARKER FOR VISCERAL METASTASIS IN METASTATIC CASTRATION-RESISTANT PROSTATE CANCER (MCRPC) Jie-Fu Chen, Hao Ho, Elisabeth Hodara, Alexandar Ureno, Ann Go, Elizabeth Kaufman, Margarit Sievert, Daniel Luthringer, Jiaoti Huang, Ker-Chau Li, Zunfu Ke, Leland Chung, Hsian-Rong Tseng, and Edwin Posadas Jie-Fu ChenJie-Fu Chen More articles by this author , Hao HoHao Ho More articles by this author , Elisabeth HodaraElisabeth Hodara More articles by this author , Alexandar UrenoAlexandar Ureno More articles by this author , Ann GoAnn Go More articles by this author , Elizabeth KaufmanElizabeth Kaufman More articles by this author , Margarit SievertMargarit Sievert More articles by this author , Daniel LuthringerDaniel Luthringer More articles by this author , Jiaoti HuangJiaoti Huang More articles by this author , Ker-Chau LiKer-Chau Li More articles by this author , Zunfu KeZunfu Ke More articles by this author , Leland ChungLeland Chung More articles by this author , Hsian-Rong TsengHsian-Rong Tseng More articles by this author , and Edwin PosadasEdwin Posadas More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.2209AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Patients with metastatic castration-resistant prostate cancer (mCRPC) who develop visceral metastasis (VM) have poorer clinical outcomes in comparison to those without VM. Currently, VM are discovered late in the disease course clinical course of mCRPC-VM and this aggressive natural history typically culminates in organ failure. There are no existing tests that identify men at risk for VM other than radiography. Our team performed circulating tumor cell (CTC) enumeration using NanoVelcro CTC Assay (CytoLumina, Los Angeles, CA) on prostate cancer patients across the spectrum of metastatic states: no metastasis, non-visceral metastasis, and VM. We identified an association between the presence of very-small-nuclear CTCs (vsnCTCs, DAPI+/Cytokeratin+/CD45- with nuclear size < 8.5μm) and VM. Serial enumeration studies suggested the emergence of vsnCTCs occurred before the detection of VM (Chen JF et al. Cancer. 2015). We then hypothesized that presence of vsnCTC signals the presence of VM and has predictive and prognostic value with respect to VM. METHODS We identified mCRPC patients who had progressed through next generation hormonal maneuvers such as abiraterone, enzalutamide, or an equivalent drug. Serial blood specimens were used for vsnCTC enumeration using NanoVelcro CTC Assay as previously published. The vsnCTC counts were related to the presence and development of VM (evaluated by radiography) as well as the response to anti-cancer treatment. RESULTS Blood specimens were identified from 28 patients who met the eligibility criteria; 16/28 patients presented with VM and 12/28 had bone-only disease at their first CTC enumeration. Five out of 12 non-VM patients developed VM during follow-up, and vsnCTCs were detected 86-196 days prior to radiographic detection of VM (true positive); 3/12 had vsnCTCs detected but no VM was found by the time of analysis (false positive). None of the vsnCTC(-) patients developed VM. vsnCTCs were detected in 21/21 VM patients compared to 3/12 non-VM patients. Reduction of vsnCTC count occurred at initiation of anti-cancer treatment; transition from vsnCTC(-) to vsnCTC(+) was seen prior to progression under the treatment. CONCLUSIONS vsnCTC is associated with the presence of VM and is a potential biomarker for predicting the development of VM and monitoring the treatment response in mCRPC. Transition from vsnCTC(-) to vsnCTC(+) was associated with the development of VM and progression under the treatment. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e78 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Jie-Fu Chen More articles by this author Hao Ho More articles by this author Elisabeth Hodara More articles by this author Alexandar Ureno More articles by this author Ann Go More articles by this author Elizabeth Kaufman More articles by this author Margarit Sievert More articles by this author Daniel Luthringer More articles by this author Jiaoti Huang More articles by this author Ker-Chau Li More articles by this author Zunfu Ke More articles by this author Leland Chung More articles by this author Hsian-Rong Tseng More articles by this author Edwin Posadas More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Very small nuclear circulating tumor cell (vsnCTC) as a putative biomarker for visceral metastasis in metastatic castration-resistant prostate cancer (mCRPC).

64 Background: Patients with metastatic castration-resistant prostate cancer (mCRPC) who develop visceral metastasis (VM) have a poorer clinical outcome in comparison to those without VM. Their clinical course is aggressive and culminates in organ failure as this process is often discovered late in the disease course. There are no existing tests that identify men at risk for VM. Our team has identified an association between the presence of very small nuclear circulating tumor cells (vsnCTCs) and VM. We hypothesized that vsnCTC that can predict the development of VM and monitor the response to anticancer treatment. Methods: In our database we identified mCRPC patients who had progressed through next generation hormonal maneuvers such as abiraterone, enzalutamide, or an equivalent drug. Serial blood specimens were used for vsnCTC enumeration using published methods. The vsnCTC counts were related to the presence and development of VM as well as the response to anticancer treatment. Results: Blood specimens were identified from 28 patients who met the eligibility criteria; 16/28 patients presented with VM and 12/28 had bone-only disease at their first CTC enumeration. Five out of 12 non-VM patients developed VM during follow-up, and vsnCTCs were detected 86-196 days prior to radiographic detection of VM (true positive); 3/12 had vsnCTCs detected but no VM was found by the time of analysis (false positive). None of the vsnCTC(-) patients developed VM. vsnCTCs were detected in 21/21 VM patients compared to 3/12 non-VM patients. Reduction of vsnCTC count occurred at initiation of anticancer treatment; transition from vsnCTC(-) to vsnCTC(+) was seen prior to progression under the treatment. Conclusions: vsnCTC is associated with the presence of VM and is a potential biomarker for predicting the development of VM and monitoring the treatment response in mCRPC. Transition from vsnCTC(-) to vsnCTC(+) was associated with the development of VM and progression under the treatment.

Recommendations on the management of controversies in advanced castrate-resistant prostate cancer

ContextControversies and uncertainties among integral management of advanced castration resistant prostate cancer continue to exist despite the number of evidence based clinical practice guidelines published with high international consensus. ObjectiveTo develop a document that reviews the management of controversies in advanced castration resistant prostate cancer, with recommendations from the definition, to the management in hormonal maneuvers, first-line treatment and second-line with new treatments as cabazitaxel or abirarerone and the multidisciplinary approach of the pathology with the goal of finding the most efficient, best time to act and safety. Evidence AcquisitionTwo meetings of a multidisciplinary group of experts involved in the management of this disease (oncologist and urologist) where pooled analysis of original literature and reached consensus document of recommendations on castration resistant prostate cancer, reviewing and attempting to address the current controversies of the disease. Evidence SynthesisThis document is endorsed by the corresponding Scientific Associations and Working Groups involved in the current management of Genitourinary Tumours: the Spanish Association of Urology (AEU) with the Uro-Oncoloy Group (GUO) and the Spanish Oncology of Genitourinary Group (SOGUG). ConclusionsWith the adaptation and implementation of this Document of Recommendations for clinical practice are available for the first time, a real road map for quality, efficiency and safety in the management of patients with CRPC.

Recomendaciones sobre el manejo de controversias en cáncer de próstata avanzado resistente a la castración

ContextControversies and uncertainties among integral management of advanced castration resistant prostate cancer continue to exist despite the number of evidence based clinical practice guidelines published with high international consensus. ObjectiveTo develop a document that reviews the management of controversies in advanced castration resistant prostate cancer, with recommendations from the definition, to the management in hormonal maneuvers, first-line treatment and second-line with new treatments as cabazitaxel or abirarerone and the multidisciplinary approach of the pathology with the goal of finding the most efficient, best time to act and safety. Evidence AcquisitionTwo meetings of a multidisciplinary group of experts involved in the management of this disease (Oncologist and Urologist) where pooled analysis of original literature and reached consensus document of recommendations on castration resistant prostate cancer, reviewing and attempting to address the current controversies of the disease. Evidence SynthesisThis document is endorsed by the corresponding Scientific Associations and Working Groups involved in the current management of Genitourinary Tumours: the Spanish Association of Urology (AEU) with the Uro-Oncoloy Group (GUO) and the Spanish Oncology of Genitourinary Group (SOGUG). ConclusionsWith the adaptation and implementation of this Document of Recommendations for clinical practice are available for the first time, a real road map for quality, efficiency and safety in the management of patients with CRPC.

Testosterone levels as a prognostic factor for survival in patients with castrate-restistant prostate cancer (CRPC).

e15159 Background: To analyze the prognostic value for survival of the absolute levels of serum testosterone in patients under the definition of CRPC (PSA and/or clinical progression with a testosterone level below 50 ng/dL). Methods: 49 patients were included in 4 non-hormonal first line phase II-III trials in our institution since August 2006 until Jan 2012 for metastatic CRPC. Inclusion criteria of those trials uniformly required castrate levels of testosterone. Survival was calculated since the date of entrance in the trial. Results: Median age was 71 years (53-89). 9/49 (18%) of the patients had visceral metastases. Median PSA was 66.7 U/L (0.1-936). Median testosterone level was 11.54 ng/dL (range 0.2-49.9). All patients had metastatic prostate cancer, previous treatment consisted of at least 2 hormonal maneuvers (adding or stopping antiandrogen for a wash-up period of 42 days for bicalutamide). All patients received at least one line of chemotherapy for CRPC as part of the trial or after the completion of the trial. Median survival was 21.85 months. For 26 patients with a serum testosterone level below the median value, median survival was 17 months and 35.45 months for those patients with a testosterone level over 11.51 ng/dL (p value 0.036). Conclusions: Testosterone serum levels even under castration level (below 50 ng/dL) were a prognostic factor for survival in patients with metastatic prostate cancer considered castration resistant.

Metástasis en senos paranasales secundaria a adenocarcinoma prostático

To report a new case of exceptional metastases from a prostatic carcinoma. 64-year-old male with nine months history of disseminated prostate cancer, taking hormonal treatment and biphosphonates, who presents with rising PSA, facial dysesthesia and left exophtalmos. MRI recognizes the existence of a solid mass in the right maxillary sinus with involvement of the ipsilateral orbital floor, and another one in the left frontal sinus invading the roof of the ipsilateral orbit and also with orbital extraconal involvement. Once the diagnosis was established hormonal maneuvers were performed and chemotherapy with docetaxel was administered achieving at the start of treatment measurable disease stabilization with biochemical remission of PSA levels, followed posteriorly by progression without changes in the metastatic images. Currently new cytoreductive therapy with docetaxel has been initiated. 1% of the prostatic tumors involve the head in their evolution. Most frequent metastases are localized in the brain and meninges, being the involvement of paranasal sinuses and ocular orbit extraordinary. The importance of these comes from the extension to the orbit and the eye in vicinity. Second line hormonal maneuvers, local radiotherapy and systemic chemotherapy will be necessary for control, although results are discouraging. In general, prognosis is poor, with short survival.

Breast Cancer Chemotherapy

Chemotherapy can be an integral component of the adjuvant management strategy for women with early-stage breast cancer. Modern adjuvant strategies now comprises one or more chemotherapy agents, hormonal maneuvers, immunotherapy agents, or experimental agents. The use of adjuvant chemotherapy is generally based on estimates of an individual's risk of recurrence and the expected benefit of therapy. However, risk-benefit calculations have recently become increasingly sophisticated as a result of advances in genetic testing and molecular marker identification as well as ongoing refinements in chemotherapy strategies. In this article we will review the role of important prognostic and predictive factors and the rationale for adjuvant systemic therapy and modern chemotherapy regimens in the management of women with early-stage breast cancer.

Management of Advanced Prostate Cancer After First-Line Chemotherapy

Hormone refractory prostate cancer (HRPC) causes substantial morbidity and mortality. There are increasing options for both first- and second-line therapy in the palliative treatment of patients with HRPC. Medications to control symptoms should first be optimized in patients with late-stage disease, and radiotherapy applied to dominant painful bone lesions. Docetaxel, mitoxantrone, satraplatin, and ixabepilone are active chemotherapeutic agents in the first- and/or second-line setting for patients with HRPC, and this may be true also of older drugs such as oral cyclophosphamide and vinorelbine. Radioisotopes such as strontium and samarium are useful for treatment of more generalized bone pain. Third-line hormonal maneuvers including glucocorticoids, ketoconazole, and estrogens can lead to further palliation in some patients, and there are provocative data that chemotherapy might restore hormonal sensitivity in a subset of patients.

Prior Estrogen Therapy as a Predictor of Response to Subsequent Estramustine-Based Chemotherapy in Patients with Androgen-Independent Prostate Cancer

BackgroundHormone-refractory prostate cancer (HRPC) has modest response rates to second-line estrogenic agents such as diethylstilbestrol and the herbal product PC SPES. Estramustine phosphate (EMP) is a microtubule inhibitory agent with estrogenic properties commonly used in patients with metastatic HRPC. To determine whether previous response to second-line estrogen therapy would predict subsequent response to EMP-based chemotherapy, a retrospective study was conducted. Patients and MethodsPatients with HRPC previously treated with second-line estrogenic therapy who subsequently received EMPbased chemotherapy were enrolled in a retrospective analysis. The progression of disease or response to treatment was determined with use of standard prostate-specific antigen (PSA) criteria and Response Evaluation Criteria in Solid Tumors. ResultsSeventy-eight patients were included in the analysis. Twenty-five patients with disease progression after receiving estrogen therapy received subsequent EMP-based chemotherapy. Overall, initial PSA response to any estrogen therapy was 54%. The overall PSA response to EMP-based chemotherapy was 60%, and the objective response was 36%. The PSA response to subsequent EMP-based chemotherapy was independent of patients having a previous response to estrogen therapy (70% vs. 53%; P = 0.68). The median overall survival for patients receiving estrogenic therapy and subsequent EMPbased chemotherapy was 12.7 months. ConclusionPrevious response to second-line hormonal maneuvers with estrogen therapy does not predict subsequent response to EMP-based chemotherapy.

Embryonic and fetal programming of physiological disorders in adulthood

In the past decade, data from numerous epidemiological studies have indicated strong inverse associations between birth weight and risk of coronary heart disease, hypertension, type 2-diabetes, and other diseases in adulthood. The "Barker hypothesis" thus postulates that a number of organ structures and functions undergo programming during embryonic and fetal life. This developmental programming determines the set points of physiological and metabolic responses in adult life. Alterations of nutrient availability during gestation may lead to developmental adaptations, via hormonal maneuvers by the embryo and fetus that readjust these set points. These adaptive measures have short-term benefits to the embryo and fetus, so that the newborn will be better prepared for the adverse environment (e.g., undernutrition). However, adequate nutritional support during postnatal life that enables catch-up growth may create metabolic conflicts that predispose the adult to aberrant physiological functions and, ultimately, increased risk of disease. It is plausible that other adverse in utero conditions, including exposure to developmental toxicants, may similarly alter adult disease susceptibility. This article provides an overview of the Barker hypothesis, its supporting evidence, the current advances in understanding the biological mechanisms underlying this phenomenon, and its implications for developmental toxicology.

Efficacy of peripheral androgen blockade on prostate cancer: Results of CALGB 9782

4559 Background: The treatment of patients with elevated PSA after definitive local therapy continues to be elusive. Many patients are reluctant to undergo androgen suppression therapy due to long-term effects. Enthusiasm has been seen for peripheral androgen blockade for such patients. Methods: We enrolled 101 patients with a climbing PSA after definitive local therapy in a mult-institutional trial. All patients had undergone previous definitive therapy defined as either a radical prostatectomy or radiation therapy. All patients had a rising PSA, above 1 ng/ml, with no detectable evidence of recurrent disease. CT and bone scans were negative. Patients received a combination of oral therapy consisting of Finasteride, at a dose of 5 mg/day, and Flutamide, at a dose of 250 mg TID. Results: The median age was 71, with a median baseline testosterone level of 322 ng/dl. A >80% PSA decline was seen in 91/94(97%) of the patients. The other three patients had drops of 77%, 73% and 38%, all of which were maintained for at least 28 days. The median time to nadir of PSA was 3.2 months. Currently, 64 patients remain on therapy with a median follow up of 33 months. Only 21 patients have progressed through this therapy, and some of these have responded to additional hormonal maneuvers, such as Flutamide withdrawal and gonadal androgen deprivation. The toxicity is very mild, with almost no reported grade 3/4 toxicity, and most grade 2 toxicity reported at <5% level. Conclusions: The combination of Finasteride and Flutamide is highly effective in suppressing PSA levels in patients with serologic progression after local therapy. Median response duration has not been reached at nearly 3 years. Its apparent efficacy and favorable toxicity profile suggest that further investigation in randomized trials may be warranted. No significant financial relationships to disclose.

Efficacy of peripheral androgen blockade on prostate cancer: Results of CALGB 9782

4559 Background: The treatment of patients with elevated PSA after definitive local therapy continues to be elusive. Many patients are reluctant to undergo androgen suppression therapy due to long-term effects. Enthusiasm has been seen for peripheral androgen blockade for such patients. Methods: We enrolled 101 patients with a climbing PSA after definitive local therapy in a mult-institutional trial. All patients had undergone previous definitive therapy defined as either a radical prostatectomy or radiation therapy. All patients had a rising PSA, above 1 ng/ml, with no detectable evidence of recurrent disease. CT and bone scans were negative. Patients received a combination of oral therapy consisting of Finasteride, at a dose of 5 mg/day, and Flutamide, at a dose of 250 mg TID. Results: The median age was 71, with a median baseline testosterone level of 322 ng/dl. A >80% PSA decline was seen in 91/94(97%) of the patients. The other three patients had drops of 77%, 73% and 38%, all of which were maintained for at least 28 days. The median time to nadir of PSA was 3.2 months. Currently, 64 patients remain on therapy with a median follow up of 33 months. Only 21 patients have progressed through this therapy, and some of these have responded to additional hormonal maneuvers, such as Flutamide withdrawal and gonadal androgen deprivation. The toxicity is very mild, with almost no reported grade 3/4 toxicity, and most grade 2 toxicity reported at <5% level. Conclusions: The combination of Finasteride and Flutamide is highly effective in suppressing PSA levels in patients with serologic progression after local therapy. Median response duration has not been reached at nearly 3 years. Its apparent efficacy and favorable toxicity profile suggest that further investigation in randomized trials may be warranted. No significant financial relationships to disclose.

Novel therapeutic strategies for androgen-independent prostate cancer: An update

Close to 30,000 men will die from prostate cancer in the United States in 2003. Hormonal ablation, the basis of systemic therapy, will invariably fail to control the progression of metastatic prostate cancer in the long run. For many years the only available therapeutic modalities for patients with metastatic androgen independent prostate cancer have been second-line hormonal maneuvers with estrogens or steroids and chemotherapy. So far, chemotherapy has been shown to confer adequate palliation but no overall survival benefit in prospective randomized controlled trials, and the only chemotherapy drugs approved by the US Food and Drug Administration are mitoxantrone and estramustine. Novel treatment strategies that aim at specific signaling pathways, apoptosis, differentiation, or specific membranous targets are being developed. Such new therapeutic modalities, along with recent data on immunotherapy and bone targeting strategies, will be reviewed here.

Low-dose continuous oral fosfestrol is highly active in 'hormone-refractory' prostate cancer

Although not clearly defined, 'hormone refractory' prostate cancer implies disease progression after orchiectomy +/- antiandrogens. Patients in this setting are usually offered chemotherapy protocols which often lead to significant toxicity and expense. In search of a well-tolerated, active, third-line treatment, we have attempted to prolong hormonal maneuvers by using low-dose estrogen therapy. Thirty-eight patients with evidence of disease progression (as indicated by 2 consecutively rising PSA determinations) after > or = 2 hormonal treatments (including surgical or chemical orchiectomy and a median of 3 prior treatment lines) received fosfestrol 100 mg t.i.d. per os in a continuous schedule until the appearance of progressive disease or excessive toxicity. Response was assessed by serial PSA levels. Complete response (CR) was defined as normalisation and partial response (PR) as a > or = 50 decrease of PSA levels for longer than one month. The median duration of prior treatment was 20 months and the median PSA at fosfestrol start was 126 ng/ml (range 8-12,800); symptoms (pain) were present in 73% of patients. CR + PR were observed in 79% (95% confidence interval: 66%-92%). The median time to progression was seven months. Pain remained stable or improved in 34% and 53%, respectively, of symptomatic patients with PSA response. Toxicity included worsening of gynecomastia, peripheral edema, and deep vein thrombosis (8%). No treatment-related deaths occurred. Uni- and multivariate analyses failed to identify predictive factors for response. PSA response was associated with significantly longer survival (13 vs. 7 months, P < 0.05 by Mantel-Haentzel). FOSF produces high rates of PSA-determined and symptomatic response in 'hormone-refractory' prostate cancer. Toxicity and ease of administration compare favorably with those reported for CHT regimens used in this setting. The role of estrogens in prostate cancer should be redefined.

Prostate cancer.

Prostate cancer accounted for over 41,000 deaths in the United States in 1996. Prostate-specific antigen (PSA) screening is capable of detecting prostate cancer and appears to detect cancers that are both clinically significant as well as organ-confined, and therefore potentially curable. The positive predictive value of PSA value has been increased by the use of the free-to-total PSA ratio. The early detection of a large number of nonpalpable tumors has mandated the development of new risk assessment schemas, which include nomograms and equations in which Gleason score, PSA, and clinical stage play a prominent role. Definitive answers to the question of watchful waiting versus intervention await conclusion of the prostate cancer intervention-versus-observation trial. For both radical prostatectomy and radiation therapy, one means of potentially reducing the risk of relapse is the use of androgen deprivation. Neoadjuvant androgen deprivation prior to surgery results in a lower incidence of positive surgical margins, but impact on survival is unknown. By contrast, the use of concurrent androgen deprivation appears to be associated with enhanced survival in patients treated with definitive radiotherapy. For good risk tumors, modem brachytherapy results in freedom from biochemical relapse rates similar to those observed with surgery and external beam radiation therapy. The best therapy for patients with positive margins or serologic progression, including radiation therapy, remains to be identified. The widespread availability of PSA testing has led to an empirically driven redefinition of advanced disease and includes patients with earlier stage disease in which primary treatment has failed. In these patients, debate remains as to whether combined androgen deprivation is superior to monotherapy. A comparison of flutamide with bicalutamide awaits maturation of survival data. The utility of antiandrogen withdrawal in patients with progressive disease despite androgen deprivation has been confirmed. Thereafter, second-line hormonal maneuvers may be appropriate. In patients with truly hormone refractory prostate cancer, a variety of nonhormonal agents, including estramustine-based therapy, suramin, mitoxantrone, and doxorubicin-based regimens have demonstrated activity and remain as options.

Second-line hormonal therapy for advanced prostate cancer: a shifting paradigm.

To discuss the evolution of new concepts in the Use of second-line hormonal therapy for patients with progressive prostate cancer despite androgen deprivation. Pertinent contemporary prostate-specific antigen (PSA)-based reports of the utility of secondary hormonal maneuvers after treatment with combined androgen blockade (CAB) were reviewed. The use of PSA as an end point in hormonerefractory prostate cancer (HRPC) trials is more widely accepted, but still remains somewhat controversial. Using PSA as an end point, it is clear that a variety of secondary hormonal maneuvers can result in responses. Antiandrogen withdrawal is efficacious in approximately 20% of patients and can be observed with a variety of antiandrogens, including flutamide, bicalutamide, and megestrol acetate. A variety of regimens, including megestrol, bicalutamide, glucocorticoids, aminoglutethimide, and ketoconazole, retain activity (14% to 75% PSA response proportion) even in patients who have failed to respond to CAB and flutamide withdrawal. Once CAB (suppression of gonadal and adrenal androgen) is undertaken, further hormonal maneuvers remain efficacious in some patients with progressive prostate cancer. Antiandrogen withdrawal is now a mandatory maneuver before proceeding to other regimens. It is clear that certain patients will continue to respond to hormonal maneuvers even after antiandrogen withdrawal. An understanding of the molecular basis of these responses may result in the development of a more targeted therapy in the future.

Importance of continued testicular suppression in hormone-refractory prostate cancer.

Patients in whom prostate cancer progresses despite testicular androgen ablation are generally said to have cancers that have become resistant to hormonal maneuvers. If androgen suppression has been pharmacologic, this therapy is often stopped before consideration of other systemic treatments. This exploratory study sought clinical correlates of experimental evidence that there may be substantial acceleration of tumor growth after cessation of androgen suppression. A retrospective multivariate analysis was performed on survival data for 341 patients treated on four clinical trials of secondary therapy for hormone-refractory prostate cancer. Factors included in the model were recent weight loss, age, performance status, disease site (soft tissue v bone-dominant), prior radiotherapy, and continued androgen suppression v discontinued exogenous endocrine therapy. Recent weight loss, age, performance status, and disease site were important prognostic factors for survival duration in hormone-refractory prostate cancer. Correcting for these factors, continued testicular androgen suppression was also an important predictor of survival duration in all data sets examined. This retrospective study showed a modest advantage in survival duration for men with hormone-refractory prostate cancer who continued to receive testicular androgen suppression. The hypothesis that continued hormonal maneuvers can still affect survival in this group warrants examination in prospective trials.

The Use of Endocrine Therapy

Endocrine therapy is still a mainstay in the treatment of metastatic breast cancer. It has been observed that about one third of women with metastatic breast cancer will respond to endocrine therapy. This response rate is surprisingly consistent for a wide variety of endocrine approaches, with a few exceptions, such as the use of corticosteroids, androgens, or danazol for which the response rate appears lower. Endocrine therapy is, in general, considerably less toxic than single or combination chemotherapy, but toxicities within the endocrine therapies may vary considerably. Thus, the choice and optimal sequencing of endocrine maneuvers relate largely to minimizing toxicity and optimizing total duration of benefit. A number of newer endocrine approaches including the antiestrogens and aminoglutethimide have recently provided a variety of less toxic choices. Even more recently, compounds such as the LHRH agonists and antiandrogens are being tested, although their use remains experimental. Combinations of two or more endocrine therapies or of chemotherapy and endocrine therapy are currently, also a subject of considerable interest. No studies to date, however, have shown a clear advantage to concurrent chemotherapy endocrine combinations or to the use of two or more concurrent hormonal maneuvers, with the possible exception of the combination of prednisolone with tamoxifen or with oophorectomy, which has improved overall survival in two trials.