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To assess ultrahigh (UH; prostate-specific antigen [PSA] levels ≥50 ng/ml) patient outcomes by comparison to other high-risk patient outcomes and to identify outcome predictors.Prostate cancer patients (PCP) from two Phase III Radiation Therapy Oncology Group clinical trials (studies 9202 and 9413) were divided into two groups: high-risk patients with and without UH baseline PSA levels. Predictive variables included age, Gleason score, clinical T stage, Karnofsky performance score, and treatment arm. Outcomes included overall survival (OS), distant metastasis (DM), and biochemical failure (BF). Unadjusted and adjusted hazard ratios (HRs) were calculated using either the Cox or Fine and Gray's regression model with associated 95% confidence intervals (CI) and p values.There were 401 patients in the UH PSA group and 1,792 patients in the non-UH PSA PCP group of a total of 2,193 high-risk PCP. PCP with UH PSA were found to have inferior OS (HR, 1.19; 95% CI, 1.02-1.39, p = 0.02), DM (HR, 1.51; 95% CI, 1.19-1.92; p = 0.0006), and BF (HR, 1.50; 95% CI, 1.29-1.73; p0.0001) compared to other high-risk PCP. In the UH cohort, PSA level was found to be a significant factor for the risk of DM (HR, 1.01; 95% CI, 1.001-1.02) but not OS and BF. Gleason grades of 8 to 10 were found to consistently predict for poor OS, DM, and BF outcomes (with HR estimates ranging from 1.41-2.36) in both the high-risk cohort and the UH cohort multivariable analyses.UH PSA levels at diagnosis are related to detrimental changes in OS, DM, and BF. All three outcomes can be modeled by various combinations of all predictive variables tested.

We evaluated whether posttreatment prostatic-specific antigen doubling time (PSADT) was predictive of prostate cancer mortality by testing the Prentice requirements for a surrogate endpoint.We analyzed posttreatment PSA measurements in a cohort of 1,514 men with localized prostate cancer (T2c-4 and PSA level150 ng/mL), treated and monitored prospectively on Radiation Therapy Oncology Group Protocol 92-02. From June 1992 to April 1995, men were randomized to neoadjuvant androgen deprivation and 65-70 Gy of radiation therapy (n = 761), or in combination with 24 months of adjuvant androgen deprivation (n = 753). Using an adjusted Cox proportional hazards model, we tested if PSADT was prognostic and independent of randomized treatment in this cohort. The endpoints were time to PSADT (assuming first-order kinetics for a minimum of 3 rising PSA measurements) and cancer-specific survival (CSS).After a median follow-up time of 5.9 years, randomized treatment was a significant predictor for CSS (p(Cox) = 0.002), PSADT6 months (p(Cox)0.001), PSADT9 months (p(Cox)0.001), and PSADT12 months (p(Cox)0.001) but not for PSADT3 (p(Cox) = 0.4). The significant posttreatment PSADTs were also significant predictors of CSS (p(Cox)0.001). After adjusting for T stage, Gleason score and PSA, all of Prentice's requirements were not met, indicating that the effect of PSADT on CSS was not independent of the randomized treatment.Prostatic specific antigen doubling time is significantly associated with CSS, but did not meet all of Prentice's requirements for a surrogate endpoint of CSS. Thus, the risk of dying of prostate cancer is not fully explained by PSADT.

Purpose: Radiation Therapy Oncology Group (RTOG) Protocol 92–02 was a randomized trial testing long-term (LT) adjuvant androgen deprivation (AD) after initial AD with external-beam radiotherapy (RT) in patients with locally advanced prostate cancer (PC; T2c-4) and with prostate-specific antigen level less than 150 ng/mL. Patients and Methods: Patients received a total of 4 months of goserelin and flutamide, 2 months before and 2 months during RT. A radiation dose of 65 to 70 Gy was given to the prostate and a dose of 44 to 50 Gy to the pelvic lymph nodes. Patients were randomly assigned to receive no additional therapy (short-term [ST]AD-RT) or 24 months of goserelin (LTAD-RT); 1,554 patients were entered onto the study. Results: The LTAD-RT arm showed significant improvement in all efficacy end points except overall survival (OS; 80.0% v 78.5% at 5 years, P = .73), compared with the STAD-RT arm. In a subset of patients not part of the original study design, with tumors assigned Gleason scores of 8 to 10 by the contributing institutions, the LTAD-RT arm had significantly better OS (81.0% v 70.7%, P = .044). There was a small but significant increase in the frequency of late radiation grades 3, 4, and 5 gastrointestinal toxicity ascribed to the LTAD-RT arm (2.6% v 1.2% at 5 years, P = .037), the cause of which is not clear. Conclusion: The RTOG 92–02 trial supports the addition of LT adjuvant AD to STAD with RT for T2c-4 PC. In the exploratory subset analysis of patients with Gleason scores 8 to 10, LT adjuvant AD resulted in a survival advantage.

The natural history of prostate cancer has long been related to the male hormone testosterone, and treatment has focused on depletion of this androgen to slow or prevent growth of prostate cancer tissue. It has become clear recently, however, that more than androgens influence the progression of prostate cancer, with recent interest focusing on the gonadotropin, follicle-stimulating hormone (FSH). Research of the last decade has found that FSH is produced in and FSH receptors are expressed in the prostate. Investigators have found as well that production of FSH is altered in prostate cancer: FSH levels are increased and receptor production raised in the cancerous prostate. It also has been shown that there are endogenous compounds such as prostatic inhibin peptin that can modulate FSH levels. All of these findings are outlined in this paper, and suggest that FSH may affect the pathogenesis and progression of prostate cancer and that altering FSH production may prove to be an active therapeutic maneuver.

Purpose: Current therapy for locally advanced prostate cancer is suboptimal. A treatment regimen was designed to improve systemic control by neoadjuvant targeting of hormone-sensitive and -insensitive micrometastatic disease and to improve local control by escalating the biologic effective dose to the prostate using estramustine (EMP) concurrently with radiotherapy. Patients and Methods: Eighteen patients with locally advanced prostate cancer (Stages T3/T4 or T1c/T2b/T2c with a Gleason score of ≥7 and a serum PSA >15 ng/ml) were entered onto this trial. Therapy consisted of two 21-day cycles of oral estramustine (10 mg/kg/day) in three divided doses and oral etoposide (50 mg/m 2 /day, in two divided doses), followed by concurrent estramustine (10 mg/kg/day, PO) and three-dimensional conformal radiotherapy. Results: Two patients required discontinuation of chemotherapy due to development of Grade 3 and 4 toxicity. All others completed both components of therapy per protocol guidelines. Minor toxicities included alopecia (100% of patients), anemia (69%), leukopenia (37%), thrombocytopenia (19%), and nausea (6%) but did not require dose modifications. There were no fatalities. Actuarial 3-year overall survival and disease-free survival (DFS) were 88% and 73%, respectively. Local control rate, assessed by repeated prostate biopsies at 18 months post completion of therapy, was 71%. Conclusion: The described regimen is well tolerated, and preliminary efficacy data are encouraging. The underlying concepts of early targeting of both hormone-sensitive and -insensitive micrometastatic clones, in combination with aggressive local therapy, warrant further investigation.

Purpose: To assess the impact of race on biochemical freedom from recurrence in patients with early-stage prostate cancer treated either by radical prostatectomy or radiation therapy. Methods: Between July 1989 and December 1994, 693 patients with early-stage prostate cancer were treated with radiation (302 patients) or by radical prostatectomy (391 patients) at Barbara Ann Karmanos Cancer Institute/Wayne State University. Stage, Gleason score, race, pretreatment PSA, and follow-up PSA values were abstracted. There were 387 Caucasian males (CM) and 306 African-American males (AAM). None of the patients received hormone therapy. Radiation therapy was delivered using photon irradiation (249 patients, median dose 69 Gy) or mixed neutron/photon irradiation (53 patients, median dose 10 NGy + 38 PGy). Median follow-up was 36 months (range 2–70) for CM and 35 months (range 1–70) for AAM. Results: Thirty-seven percent of patients treated surgically were AAM, compared to 53% in the radiation group ( p = 0.0001). AAM had a higher median prostate-specific antigen (PSA) than CM (9.78 ng/ml vs. 8.0 ng/ml, p = 0.01). Thirty-three percent of AAM had a pretreatment PSA greater than 15 ng/ml compared to 20% of CM ( p = 0.00001). Disease-free survival (DFS) by race was equivalent at 36 months, 81% for CM and 77% for AAM ( p = NS). For patients with PSA ≤ 15, DFS rates were 87% and 85% for CM and AAM, respectively. DFS rates for patients with PSA > 15 were 61% for CM and 64% for AAM ( p = NS). Significant prognostic factors on multivariate analysis included pretreatment PSA ( p = 0.0001) and Gleason score ( p = 0.0001). Conclusion: Race does not appear to adversely affect biochemical disease-free survival in males treated for early-stage prostate cancer. African-American males with early-stage prostate cancer should expect similar biochemical disease-free survival rates to those seen in Caucasian males.

The design and construction of a unique superconducting cyclotron for use in fast neutron radiation therapy is described. The clinical results obtained in the treatment of adenocarcinoma of the prostate with this accelerator are presented. Future use of the boron neutron capture reaction as a means of enhancing fast neutron therapy in the treatment of patients with brain tumors (glioblastoma multiforme) is also discussed.

The results of clinical trials in the treatment of adenocarcinoma of the prostate using, mixed beam neutron/photon therapy, neutrons alone and photon therapy in combination with hormone treatment are compared. These trials indicate that neutron therapy is superior to photon/hormone therapy in achieving local control. The costs of delivering these two different therapies in a large US academic radiation oncology center at Wayne State University (WSU) are compared. The cost of a full course of mixed beam therapy is $20,142 compared to $18,871 for the photon/hormone treatment. Although the WSU neutron facility is a state-of-the-art installation, it is also a prototype device; it is estimated that a modern neutron facility based on this design would operate more cost effectively reducing the cost of a course of mixed beam therapy to $ 18,532.

The mass energy-absorption coefficients and electron mass collision stopping powers have been calculated for tumors of various histologies. Eleven excised or biopsied tumor specimens were considered, including samples from two squamous cell lungcarcinomas, two sarcomas, three adenoid cystic carcinomas, two melanomas and two rectal carcinomas. The hydrogen, carbon, nitrogen and oxygen composition of the tumor samples was determined. Photon mass energy-absorption data in the energy range 1 keV to 20 MeV have been calculated using elemental mass energy-absorption coefficients previously calculated by Hubbell and Seltzer. Electron mass collision stopping powers for energies between 10 keV and 60 MeV were calculated from the values for water using the data and methodology described in ICRU Report #37. The ratio of the average mass energy-absorption coefficient of the tumor samples to the coefficient of water was found to be 0.99 across most of the energies of clinical interest (>100 keV) except for photon energies of 5 MeV and above for which the ratio dropped to 0.98. The ratio of the average electron mass collision stopping power of the tumor specimens to that of water was 0.99 for all energies.

Purpose: Understanding growth regulation in hormone-refractory prostate cancer may provide avenues for novel treatment interventions. This study was conducted to characterize the expression of the receptor (FSHR) for follicle-stimulating hormone (FSH) in androgen-independent prostate cancer cell lines and in human malignant prostate tissues.Materials and Methods: Western blotting, immunohistochemistry (IHC), and flow cytometric analysis were used to study the expression of FSHR. The effect of FSH on cell growth and clonogenicity was studied using proliferation and clonogenic assays.Results: Immunohistochemistry revealed expression of FSH in PC3 and Du145 cells. FSHR was identified in PC3 and Du145 cells, as well as in human adenocarcinoma of the prostate. The specificity of the FSHR detected on prostate cancer tissues or cells by IHC and Western blotting was confirmed by preabsorbing the antibodies with the immunizing antigens. Stimulation of these hormone-refractory cells with FSH triggered a pro...

BACKGROUND PSP94 (prostate secretory protein of 94 aa; also called PIP), one of the predominant proteins secreted into the seminal fluid, was proposed as an independent diagnostic/prognostic marker for prostate cancers. It was also shown to inhibit rat prostate cancer growth. In this study, we investigated the effect of purified PSP94 on the growth of androgen-independent human prostate cancer cells (PC3) and its potential mechanism of action. METHODS AND RESULTS PSP94, in a dose- and time-dependent manner, inhibited the growth of PC3 cells. The protein demonstrated a stronger inhibitory effect on the colony-forming ability of PC3 cells in soft agar. A daily injection of PSP94 at 5 μg/kg/body weight resulted in a 50–60% inhibition in the growth of PC3 xenografts in athymic mice. PC3 cell growth inhibition by PSP94 resulted from cell death characteristic of morphological apoptosis, which was confirmed by dual fluorescence microscopy, electron microscopy, and DNA fragmentation assays. Mechanistic studies indicated that PSP94 enhanced the expression of proapoptotic protein Bax without affecting Bcl-2 levels. CONCLUSIONS This study suggests that PSP94 may represent a novel, apoptosis-based, antitumor agent applicable to the treatment of hormone-refractory human prostate cancers. Prostate 38:118–125, 1999. © 1999 Wiley-Liss, Inc.

Bone metastases require multidisciplinary treatment, the primary goal of which is to relieve pain and improve quality of life. Among the options available, bone-seeking radioisotopes are attractive because they can treat several symptomatic metastases simultaneously. This therapy may have antitumor efficacy in addition to analgesic properties. Although the ultimate place of systemic radionuclides in the treatment of bone metastases has not been firmly established, some patients clearly benefit from these modalities.

A newly synthesized cyclic hydroxamic acid compound, BMD188 [cis-l-hydroxy-4-(l-naphthyl)-6-oc-tylpiperidine-2-one], was found to induce the apoptotic death of cultured prostate cancer cells by activating caspase-3. Orally administered BMD188 significantly inhibited the primary growth of prostate cancer cells (Dul45) orthotopically implanted into SCID mice. Mechanistic studies indicated that BMD188 did not alter the protein levels of several Bcl-2 family members. In contrast, the BMD188 effect required three essential factors: reactive oxygen species (ROS), the mitochondrial respiratory chain function, and proteases. First, the apoptosis-inducing effect of BMD188 could be blocked by ROS scavengers such as Desferal. Second, both BMD188-induced PARP cleavage as well as PC3 cell apoptosis could be dramatically inhibited by several complex-specific mitochondrial respiration blockers. The involvement of mitochondria was also supported by the observations that BMD188 dramatically altered the mitochondrial distribution and morphology without affecting the cellular ATP levels. Finally, the apoptosis-inducing effect of BMD188 in PC3 cells could be significantly inhibited by serine protease inhibitors (TPCK and TLCK) as well as by caspase inhibitors (zVAD-fmk and DEVD-CHO). Collectively, the present study suggests that BMD188 and its analogs may find clinical applications in the treatment of prostate cancer patients by inducing apoptotic death of prostate cancer cells.

BACKGROUND Integrins participate in cell-cell and cell-matrix interactions. In this study we determined whether αIIbβ3 integrin is involved in metastasis of human prostate adenocarcinoma cells. METHODS Prostate adenocarcinoma PC-3 and DU-145 cell lines express αIIbβ3. Northern blotting, 5′-RACE, and immunofluorescent localization confirmed expression of αIIb integrin in prostate adenocarcinoma cells. We used orthotopic/ectopic site of implantation and lung colonization assays in SCID mice to determine whether αIIbβ3 participates in metastatasis of tumor cells. RESULTS Immunofluorescent localization of αIIb integrin in fibronectin-adherent DU-145 and PC-3 cells is remarkably different. In DU-145 cells the integrin localizes to focal contact sites, whereas it is predominantly intracellular in PC-3 cells. Both tumor cell lines are tumorigenic when implanted subcutaneously or intraprostatically in SCID mice, but only DU-145 cells injected intraprostatically metastasize. Flow cytometry with a mAb directed to αIIbβ3 revealed higher expression of αIIbβ3 in DU-145 tumor cell suspensions isolated from the prostate when compared to DU-145 tumor cells from the subcutis. Function-blocking mAbs to αIIbβ3 inhibit lung colonization of tail vein-injected DU-145 cells. CONCLUSIONS Altogether, the data suggest that αIIbβ3 integrin participates in the metastatic progression of prostatic adenocarcinoma. Prostate 35:185–192, 1998. © 1998 Wiley-Liss, Inc.

Purpose: Radiotherapy plays a major role in the management of painful osseous metastases. This survey was conducted to study the current approaches to this clinical problem in the radiotherapy community. Methods and Materials: A questionnaire was sent to 2500 members of the American Society for Therapeutic Radiology and Oncology. It consisted of 30 multiple-choice questions regarding four hypothetical clinical scenarios likely to be encountered in daily practice. Questions related to the technique of choice [local field (LF) vs. hemibody radiotherapy (HBI)], the use of systemic radionuclides (SR), fractionation schemes, dose, the integration of modalities, and the follow-up of these patients. The analysis is based on 817 (33%) responses received regarding 3268 cases. Results: Local field is the most common form of therapy. Overall, LF was used, alone or in combination with other forms of therapy, in 54% and 74% of patients, respectively. LF was used more frequently in patients with breast cancer than in patients with prostate cancer (79% vs. 45%; p = 0.0001). Long fractionation schemes were used by 90% of physicians in 96% of cases. Short fractionation schemes were used by 7% of physicians in 4% of cases. This tendency was more pronounced in private practice than in the university or government/multidisciplinary settings (p = 0.008) and in physicians starting their practice before 1982 (p = 0.05). The most common schedule was 30 Gy in 10 fractions, used by 77% of physicians in 64% of cases. HBI was used, alone or in combination with other forms of therapy, in 1% and 2% of patients, respectively. It was used more frequently in patients with prostate cancer than in patients with breast cancer (1.2% vs. 0.1%, respectively; p < 0.0001). SR were used alone or in combination with local-field irradiation in 21% and 40% of cases, respectively. SR were used more frequently in patients with prostate cancer than in those with breast cancer (28% vs. 0.2%, respectively; p < 0.00001). The most common radionuclide in use is Sr-89 (99%) at a dose of 4 mCi (73%) or 10.8 mCi (26%). Conclusions: Although LF remains the mainstay of therapy, our results demonstrate the emergence of a new pattern of practice: LF to the painful site in combination with SR for clinically occult metastases. Despite an ongoing academic debate regarding fractionation schemes, the vast majority of American practitioners advocate long schedules.

BACKGROUND Radiation-induced necrosis (RIN) of the brain is a complication associated with the use of aggressive focal treatments such as radioactive implants and stereotactic radiosurgery. In an attempt to treat patients with central nervous system (CNS) RIN, ten patients received hyperbaric oxygen treatment (HBOT). METHODS Patients presented with new or increasing neurologic deficits associated with imaging changes after radiotherapy. Necrosis was proven by biopsy in eight cases. HBOT was comprised of 20-30 sessions at 2.0 to 2.4 atmospheres, for 90 minutes-2 hours. Sites of RIN included the brain stem (n = 2), posterior fossa (n = 1), and supratentorial fossa (n = 7). Histologic types included brain stem glioma (n = 2), ependymoma (n = 2), germinoma (n = 2), low grade astrocytoma (n = 1), oligodendroglioma (n = 1), glioblastoma multiforme (n = 1), and arteriovenous malformation (n = 1). RESULTS Initial improvement or stabilization of symptoms and/or imaging findings were documented in all ten patients studied and no severe HBOT toxicity was observed. Four patients died, with the cause of death attributed to tumor progression. Five of six surviving patients were improved by clinical and imaging criteria; one patient was alive with tumor present at last follow-up. CONCLUSIONS HBOT may prove to be an important adjunct to surgery and steroid therapy for CNS RIN. Cancer 1997; 80:2005-12. © 1997 American Cancer Society.

Quality of life is one of several endpoints commonly studied in prostate cancer treatment. It refers to how well an individual is functioning in life and his total sense of well being. There is increasing recognition that cancer therapy impacts significantly on the patient's ability to pursue relational, occupational and social interests. Fifty-one patients with clinically localized prostate cancer who had undergone transperineal permanent prostate implantation were evaluated. All patients were clinically staged as T1c or T2a and received an implant alone with Iodine 125 or Palladium 103 as definitive treatment. Six months after implant, data was collected using the European Organization for Research and Treatment of Cancer (EORTC) genitourinary group questionnaire and supplemental questions. Urinary symptoms such as nocturia, hesitancy, frequency, and dysuria were the most pronounced in the first few months after the implant and then decreased in most of patients; 40% noticed that they urinated more frequently and 17% had mild dysuria. All patients denied hematuria and none reported incontinence. Few patients reported any psychological distress or disruption in social or family life; none reported disruption in economic status or viability. All fifty-one patients said that they would have an implant again as definitive treatment. Seventy-nine percent reported an excellent quality of life post-implant. While survival is clearly a central goal of treatment for prostate cancer, the nature of this malignancy compels clinical attention to the quality of the patient's life after treatment. Sexual quality and function are maintained in the majority of patients and there is minimal interruption of their social and economic function.

A model of strontium biodistribution similar to the one created by the International Commission on Radiological Protection (ICRP) was applied for activity and absorbed dose calculations in a patient with bone metastases treated with Sr-89 strontium chloride. Metastases are represented just like all other organs and tissues collecting strontium. Data from the ICRP's standard Reference Man were used.Results include calculated time-activity data for all model compartments and for relevant target organs. Absorbed doses per unit administered activity were calculated for blood (0.036 cGy/MBq), soft tissues (0.046 cGy/MBq), bone marrow (1.15 cGy/MBq), bone surface (1.45 cGy/MBq), upper large intestine (ULI) (0.13 cGy/MBq), lower large intestine (LLI) (0.38 cGy/MBq), bladder (0.12 cGy/MBq), and metastases (37.5 cGy/MBq).Results of the absorbed dose calculations are comparable with results presented in references for specific clinical cases. Discrepancies in dose values may be effected by the size of metastases and the patient's condition.

Purpose: This study was initiated to determine the efficacy of post-prostatectomy therapeutic radiation for patients with elevated prostate specific antigen (PSA).Materials and Methods: A total of 47 patients received 66 Gy. therapeutic irradiation to the prostate bed for a PSA level greater than 0 ng./ml. postoperatively. Univariate and multivariate survival analyses were performed to identify prognostic variables.Results: At a median followup of 36 months (range 18 to 48) 83 and 33% of the patients with PSA 2 ng./ml. or less and 2 ng./ml. or greater, respectively, had no evidence of disease (p = 0.001). Pathological stage and a complete biochemical response (PSA less than 0.05 ng./ml.) were also significant prognostic variables.Conclusions: Therapeutic irradiation for patients with elevated PSA postoperatively is highly effective. At a median followup of 36 months 64% of the patients remain disease-free.

Serum-cultured rat W256 carcinosarcoma cells of the monocytoid origin undergo rapid apoptosis in response to the lipoxygenase inhibitor NDGA (nordihydroguaiaretic acid). Exogenous arachidonic acid (AA), in a time- and dose-dependent fashion, suppressed NDGA-induced W256 cell apoptosis as well as DNA fragmentation, with the maximal effect observed at approximately 25 microM. Mobilization of endogenous AA by calcium ionophore A23187 provided an even stronger and longer-lasting protection against NDGA-caused cell death. The A23187 effect on AA release as well as W256 cell death can be blocked by bromophenacyl bromide, thus suggesting involvement of phospholipase A2 activation. Serum withdrawal similarly caused W256 cells to undergo typical apoptosis, which was not rescued by several growth factors commonly found in serum. However, exogenous AA suppressed serum starvation-induced W256 cell apoptosis and significantly extended cell survival in a dose-dependent manner. Lipoxygenase products, 12(S)- and 15(S)-, but not 5(S)-hydroxyeicosatetraenoic acid (HETE), in a dose-dependent fashion, also prevented both NDGA- and serum-starvation-induced W256 cell apoptosis. AA appears to suppress W256 cell apoptosis via distinct signaling pathway(s) since it does not prevent cell death triggered by several other inducers. Examination of a panel of polyunsaturated fatty acids revealed that alpha-linolenic and linoleic acid can also suppress NDGA-induced W256 cell apoptosis. Our data suggest that AA and other polyunsaturated fatty acids and/or their metabolites may enhance tumor growth not only by promoting cell proliferation but also by suppressing apoptosis.

BACKGROUND Prostate cancer is the most commonly diagnosed neoplasm and the second leading cause of male death in this country. Multiple genetic and epigenetic factors have been implicated in the oncogenesis and progression of prostate cancer. However, the molecular mechanisms underlying the disease remain largely unknown. The major difficulty in the clinical management of prostate cancer stems from the reality that reliable and accurate diagnostic/prognostic biomarkers are not available and that effective treatment regimens for hormone-resistant prostate cancers are yet to be developed. METHODS The present review, through extensive literature research, summarizes the most recently accumulated experimental and clinical data on the relationship between apoptosis and prostate cancer. We analyze the possibility of inducing prostate cancer cell apoptosis by: 1) androgen ablation by castration or biochemical antagonists: 2) chemotherapeutic drugs or natural/synthetic chemicals; 3) manipulation of apoptosis-related oncoproteins; and 4) modulation of intracellular signal transducers. RESULTS 1) Prostate cancer, like most other solid tumors, represents a very heterogeneous entity. Most prostate cancers, at the time of clinical diagnosis, present themselves as mixtures of androgen-dependent and androgen-independent cells. 2) Most prostate cancers respond initially to androgen ablation since the population of androgen-dependent cells undergoes rapid apoptosis upon androgen withdrawal. However, androgen ablation rarely cures patients, most of whom will experience recurrence due to takeover of the tumor mass by androgen-independent tumor cells as well as the emergence of apoptosis-resistant clones as a result of further genetic alterations such as bcl-2 amplification. 3) On the other hand, although androgen-independent prostate cancer cells do not undergo apoptosis upon androgen blocking, they do maintain the appropriate molecular machinery of apoptosis. Therefore, certain conventional chemotherapy drugs can eliminate androgen-independent cancer cells by inducing apoptosis. 4) However, most drugs used in chemotherapy induce apoptosis or mediate cytotoxicity only in proliferating cancer cells. Human prostate cancer cells demonstrate very slow growth kinetics. Thus, novel chemical/natural products need be identified to eradicate those nonproliferating cancer cells. In this regard, the angiogenesis inhibitor, linomide, and a plant extract, β-lapachone, demonstrate very promising apoptosis-inducing effects on prostate cancer cells in a proliferation-independent manner. 5) An alternative way to modulate the apoptotic response is by interfering with the expression levels of essential regulatory molecule of apoptosis. Bcl-2 and p53 represent two prime targets for such manipulations. 6) Finally, modulation of signal transduction pathways (e.g., intracellular Ca2+ levels, PKC activity) involved in apoptosis may also induce and/or enhance the apoptotic response of prostate cancer cells. CONCLUSIONS Modulation of apoptotic response represents a novel mechanism-based approach which may help identify novel drugs and/or develop new therapeutic regimens for the treatment of prostate cancers. Prostate 32:284–293, 1997. © 1997 Wiley-Liss, Inc.

The integrin alphaIIb beta3 is a membrane receptor which was considered to be expressed only in cells of megakaryocytic lineage. We have shown that alphaIIb beta3 is expressed in mouse melanoma B16a cells, and in human prostate adenocarcinoma cells. The purpose of this study was to determine whether the megakaryocytic product alphaIIb beta3 was functionally expressed in other non-megakaryocyte lineage tumor cells. By using the reverse transcription polymerase chain reaction (RT-PCR), we have obtained data demonstrating that alphaIIb beta3 is expressed in a variety of tumor cell lines (17) derived from different species (human, rat and mouse) and of different histological origins (skin, blood, lung, liver, kidney, cervix, colon, bladder, breast and prostate). Immunostaining of tumor cells with a monoclonal antibody (MAb) to alphaIIb beta3 demonstrates that alphaIIb beta3 protein is also expressed in tumor cells. A protein kinase C activator PMA stimulates adhesion of tumor cells to fibronectin and fibrinogen, and this stimulated adhesion is blocked by a function-blocking MAb directed to alphaIIb beta3. Our results indicate that the megakaryocytic gene product alphaIIb beta3 integrin is widely expressed among tumor cells of non-megakaryocytic lineage, suggesting that ectopic expression of this integrin may play an important role in tumor progression.

BACKGROUND The incidence and mortality of prostate cancer are increasing at alarming rates, partially due to an aging population. Early detection of prostate cancer, using clinically sensitive procedures and/or tumor markers (e.g., prostate-specific antigen [PSA]), is of prime importance. However, the choice of therapeutic interventions for prostate cancer at the time of diagnosis is largely dependent on clinical and pathologic staging and prediction of the degree of aggressiveness of the disease. Clinically applicable prognostic markers are urgently needed to assist in the selection of optimal therapy. METHODS Literature review of the potential diagnostic and prognostic markers for human prostate cancer. RESULTS Well-established tissue prognostic indicators, including histologic grade, margin positivity, pathologic stage, intraglandular tumor extent, and DNA ploidy, are not reviewed in this paper. Recently, a number of novel markers have been identified. In this paper, we begin with a discussion of a number of well-established as well as investigational diagnostic markers and then focus on evaluation of prognostic markers. Diagnostic markers that have prognostic value and investigational prognostic markers are also discussed. CONCLUSIONS Currently, only PSA is utilized for early diagnosis and monitoring of prostate cancer. A number of potential prognostic markers warrant further investigation. Multimarker analysis is implicated. Prostate 31:264–281, 1997.© 1997 Wiley-Liss, Inc.

Objectives To identify complications of various forms of treatments for prostate cancer and their influence on patients' quality of life with the ultimate goal of suggesting a Quality of Life Questionnaire specific for prostate cancer for further validation. Methods The literature was screened for reports on the more common complications following various forms of therapy for prostate cancer. Frequencies were summarized. The scarce literature reporting on quality of life in prostate cancer was reviewed and conflicting data were discussed and reassessed. Suggested questionnaires used in other studies were critically scrutinized and the various questions recorded. Results Following radical surgery, impotence and incontinence were the most common complications reducing patients' quality of life. The literature was not uniform with regard to whether loss of sexual function was regarded as a worse complication than loss of urinary control. Following radiotherapy, intestinal problems and sexual dysfunction were the dominating side-effects. Quality of life was best preserved in surveillance-only series. Following endocrine therapy, not only impotence and hot flushes were focused upon, but also mental dysfunction and intestinal dysfunction from nonsteroidal antiandrogens; additonally, the importance of effective palliation was highlighted. A Quality of Life Questionnaire should contain general domains relevant to cancer patients, cancer-specific questions, and prostate-cancer-specific questions. The latter group includes: worry for prostate cancer and its prognosis, bone/pelvic pain, lower urinary tract symptoms, urinary incontinence, urinary diversion, bowel function, sexual function, endocrine effects, and satisfaction with medical care for prostate cancer. Conclusions A modern trial of prostate cancer treatment should be regarded as insufficient without including a validated Quality of Life Questionnaire.

PURPOSE Although androgen suppression results in a tumor response/remission in the majority of patients with carcinoma of the prostate, its potential value as an adjuvant has not been substantiated. MATERIALS AND METHODS In 1987, the Radiation Therapy Oncology Group (RTOG) initiated a randomized phase III trial of adjuvant goserelin in definitively irradiated patients with carcinoma of the prostate. A total of 977 patients had been accessioned to the study. Of these, 945 remained analyzable: 477 on the adjuvant arm and 468 on the observation arm. RESULTS Actuarial projections show that at 5 years, 84% of patients on the adjuvant goserelin arm and 71% on the observation arm remain without evidence of local recurrence (P < .0001). The corresponding figures for freedom from distant metastases and disease-free survival are 83% versus 70% (P < .001) and 60% and 44% (P < .0001). If prostate-specific antigen (PSA) level greater than 1.5 ng is included as a failure (after > or = 1 year), the 5-year disease-free survival rate on the adjuvant goserelin arm is 53% versus 20% on the observation arm (P < .0001). The 5-year survival rate (for the entire population) is 75% on the adjuvant arm versus 71% on the observation arm (P = .52). However, in patients with centrally reviewed tumors with a Gleason score of 8 to 10, the difference in actuarial 5-year survival (66% on the adjuvant goserelin arm v 55% on the observation arm) reaches statistical significance (P = .03). CONCLUSION Application of androgen suppression as an adjuvant to definitive radiotherapy has been associated with a highly significant improvement in local control and freedom from disease progression. At this point, with a median follow-up time of 4.5 years, a significant improvement in survival has been observed only in patients with centrally reviewed tumors with a Gleason score of 8 to 10.

Purpose: To examine the efficacy of postoperative radiation therapy for early-stage cervical cancer with pathologic risk factors. Methods and Materials: We reviewed the charts of 83 patients who received postoperative radiation therapy at our facility from March 1980 to November 1993 for early stage cervix cancer with positive surgical margins, positive pelvic or periaortic lymph nodes, lymphovascular space invasion, deep invasion, or for disease discovered incidently at simple hysterectomy. Twenty-eight patients received low dose rate (LDR) intracavitary radiation with or without external beam pelvic irradiation and 55 patients received external beam pelvic irradiation with high dose rate (HDR) intracavitary implants. Of these 83 patients, 66 were evaluable-20 LDR and 46 HDR patients. All patients received 45-50 Gy external beam irradiation and 20 Gy LDR equivalent intracavitary irradiation prescribed to 0.5 cm below the mucosa. Ninety percent of the LDR group and 92% of the HDR group completed treatment within < 56 days. Treatment-related toxicities were scored according to the GOG toxicity scale. Mean and median follow-up times were 101 months and 111 months (3-172 months) for the LDR group and 42 and 40 months (3-98 months) for the HDR group. Results: The 5-year disease-free survival was 89% for the LDR group and 72% for the HDR group. Local control was observed in 90% (18 out of 20) of the LDR patients and 89% (41 out of 46) of the HDR patients for an overall local control rate of 89.5%. Two of 20 LDR patients (10%) experienced recurrence (two pelvic with distant metastasis). Nine of 46 HDR patients (22%) had recurrence of disease (three pelvic, four distant metastasis, and two pelvic with distant metastasis). In the HDR group, 6 out of 16(38%) with positive lymph nodes died of disease whereas, 27 out of 30 (90%) of the patients with negative lymph nodes remain free of disease. Three of 20 (15%) LDR patients and 4 out of 46 (9%) ) HDR patients experienced Grade 2 or 3 late treatment- related complications. No patient in either group had Grade 4 or 5 complications. Pathologic risk factors were analyzed. Lymph node positivity and lymphovascular space invasion were found to be significant (p = 0.01 and p = 0.02). Positive margins, deep invasion, and age were not significant. Conclusion: Our results demonstrate the efficacy of postoperative irradiation for cervical cancer with pathologic risk factors. Overall, the local control rate was 89.5% The HDR results demonstrate that this method can be delivered safely and effectively.

Systemic radionuclide therapy is gaining popularity in the radiotherapy community and changing the management of painful osseous metastases. This form of therapy has two major advantages: (i) it addresses all sites of involvement; and (ii) selective absorption limits normal tissue dose. As a result, toxicity is reduced and the therapeutic ratio increased. The biokinetics, dosimetry, and clinical experience with these compounds are reviewed. To date, the best studied and most commonly used radionuclide is strontium-89. Large, prospectively randomized clinical trials have demonstrated its efficacy as a first-line therapy or as an adjuvant to external-beam radiotherapy. It is particularly useful when external-beam therapy options have been exhausted, and normal tissue tolerance has been reached. In metastatic prostate cancer, our recent survey suggests the formation of a new paradigm: local field external-beam radiotherapy to the painful index site in combination with prophylactic administration of systemic radionuclides for clinically occult metastases.

In Part Three of this review, we begin with an analysis of prevention strategies for prostate cancer followed by a discussion of the clinical use of molecular techniques for the evaluation and treatment of patients with clinically localized prostate cancer. New developments in neutron and photon therapy of prostate cancer are addressed as well as the use of systemic radiotherapy for the treatment of bone metastases. Finally, we conclude with the role of hormonal therapy in the treatment of prostate cancer and the current status of development of chemo therapeutic regimens for the treatment of prostate cancer.

Diagnostic and prognostic markers for prostatic cancer (PCa) include conventional protein markers (e.g., PAP, PSA, PSMA, PIP, OA-519, Ki-67, PCNA, TF, collagenase, and TIMP 1), angiogenesis indicator (e.g., factor VIII), neuroendocrine differentiation status, adhesion molecules (E-cadherin, integrin), bone matrix degrading products (e.g., ICPT), as well as molecular markers (e.g., PSA, PSMA, p53, 12-LOX, and MSI). Currently, only PSA is used clinically for early diagnosis and monitoring of PCa. The histological differential diagnosis of prostatic adenocarcinoma includes normal tissues such as Cowper's gland, paraganglion tissue and seminal vesicle or ejaculatory duct as well as pathological conditions such as atypical adenomatous hyperplasia, atrophy, basal cell hyperplasia and sclerosing adenosis. A common PCa is characterized by a remarkable heterogeneity in terms of its differentiation, microscopic growth patterns and biological aggressiveness. Most PCa are multifocal with signi ficant variations in tumor grade between anatomically separated tumor foci. The Gleason grading system which recognizes five major grades defined by patterns of neoplastic growth has gained almost uniform acceptance. In predicting the biologic behavior of PCa clinical and pathological stages are used as the major prognostic indicators. Among the cell proliferation and death regulators androgens are critical survival factors for normal prostate epithelial cells as well as for the androgen-dependent human prostatic cancer cells. The androgen ablation has been shown to increase the apoptotic index in prostatic cancer patients and castration also promotes apoptotic death of human prostate carcinoma grown in mice. The progression of PCa, similarly to other malignancies, is a multistep process, accompanied by genetic and epigenetic changes, involving phenomenons as adhesion, invasion and angiogenesis (without prostate specific features).

Apoptosis is a cell suicide program characterized by distinct morphological (cell shrinkage, membrane blebbing, pyknosis, chromatin margination, denser cytoplasmic images) and biochemical (e.g., DNA fragmentation into distinct ladders; degradation of apoptotic markers such as PARP and nuclear lamins) features. It is involved in multiple physiological processes examplified by involution of mammary tissues, embryonic development, homeostatic maintenance of tissues and organs, and maturation of the immune system, as well as in many pathological conditions represented by neurologic degeneration (Alzeimer's disease), autoimmune and inflammatory diseases, etiology of atherosclerosis, AIDS, and oncogenesis and tumor progression. Numerous molecular entities have been shown to regulate the apoptotic process. This review provides a concise summary of the recent data on the role of oncogenes/tumor suppressor genes, cytokines and growth factors/growth factor receptors, intracellular signal transducers, cell cycle regulators, reactive oxygen species or other free radicals, extracellular matrix regulators/cell adhesion molecules, and specific endonucleases and cytoplasmic proteases (the ICE family proteins) in regulating cell survival and apoptosis. Elucidation of the molecular mechanisms regulating apoptosis bears tremendous impact on enhancing our understanding of many diseases inflicting the human beings and undoubtedly brings us hope for the cure of these diseases.

Purpose: This study was initiated to assess the incidence of chronic complications and histologic and biochemical control following hyperfractioned conformal radiotherapy in patients with locally advanced prostate cancer. Methods and Materials: Between October 1991 and October 1994, 49 patients with locally advanced prostate cancer were entered on the first two dose levels of a prospective dose-escalation study using hyperfractionated three dimensional conformal radiotherapy. The first 25 patients received a minimum tumor dose of 78 Gy to the prostate and seminal vesicles in 6 weeks at 1.3 Gy, b.i.d. No increase in chronic toxicity compared with conventional radiotherapy was noted; therefore, an additional 24 patients were treated to a minimum tumor dose of 82.8 Gy to the prostate and seminal vesicles in 7 weeks at 1.15 Gy, b.i.d. Toxicity was scored according to the Radiation Therapy Oncology Group morbidity grading scale. Efficacy was assessed through scheduled postradiation prostate specific antigen values and ultrasound-guided biopsies. The median follow-up for the entire group was 20 months. Results: Thy hyperfractionated external radiation was well tolerated with minimal acute morbidity. At 30 months, the actuarial probability of Grade 2 gastrointestinal toxicity was 17%. At 30 months, the actuarial probability of Grade 2 genitourinary toxicity was 16%. There was no statistically significant difference between the two dose levels. No Grade 3 or 4 gastrointestinal or genitourinary toxicity was noted. At 12 months, 84% of patients had a prostate specific antigen ≤ 4; and 53%; ≤ 1 ng/ml. At 12 months, 71% of patients had post radiation biopsies that were either negative (55%) or showed a marked therapeutic effect (16%). Conclusion: The use of hyperfractionated conformal radiotherapy facilitated dose escalation with no increase in chronic toxicity compared to standard doses. The initial tumor response based on prostate specific antigen measurements adn postradiation biopsies is highly encouraging. Based on these results, an increase in dose to 87.4 Gy has been planned according to the schema of this ongoing dose escalation study.

Invasive bladder cancer remains a therapeutic challenge. Approximately 50% of patients treated with radical cystectomy die of metastatic disease. External beam radiation therapy when given alone has results inferior to that of surgery, and although it has shown some benefit when given in the preoperative setting, this was not verified by randomized trials. Altered fractionation radiation schemes and combined modality using a cisplatin-based combination chemotherapy with radiation have resulted in up to 60% bladder preservation.

Objectives Prostate cancer is the most frequently diagnosed cancer and the second leading cause of cancer death in males in the United States. The mortality is due mainly to distant metastasis. Therefore, predicting the prognosis of prostate cancer patients is an important clinical problem. Previously, we demonstrated that a 12-lipoxygenase (12-LOX) metabolite of arachidonic acid, 12(S)-hydroxyeicosatetraenoic acid, enhances the invasiveness of prostate cancer cells and that a 12-LOX-selective inhibitor (N-benzyl-N-hydroxy-5-phenylpentanamide) reduces experimental metastasis in animal model systems. In this study, we investigated the potential of 12-LOX as a predictor for the aggressiveness of prostate cancer. Methods The mRNA expression levels of 12-LOX in 122 matching prostate normal and cancerous tissues were measured by quantitative reverse transcription-polymerase chain reaction. Possible association between 12-LOX expression and histologic grade, pathologic and clinical stage, margin positivity, age, and race was analyzed. Results 12-LOX mRNA levels were elevated in cancer cells and the expression associated with poor differentiation and invasiveness of prostate cancer. Overall, 46 (38%) of 122 evaluable patients showed elevated levels of 12-LOX mRNA in prostate cancer tissues compared with the matching normal tissues. A statistically significantly greater number of cases were found to have an elevated level of 12-LOX among T3, high grade, and surgical margin-positive than T2, intermediate, and low grade, and surgical margin-negative prostatic adenocarcinomas. Conclusions Our data suggest that elevation of 12-LOX mRNA expression occurs more frequently in advanced stage, high-grade prostate cancer and that 12-LOX may serve as an indicator for progression and prognosis of prostate cancer. This enzyme also may be a novel target for the development of anti-invasive and antimetastatic agents.

Brachytherapy is one of the oldest techniques of radiation therapy for prostate cancer. However, its use has been controversial due to mixed results with older implant techniques and the availability of different treatment methods. New methods of brachytherapy based on improved technology and increased understanding of radiobiology hold promise for consistently improved results. This article describe the various methods of prostate brachytherapy and reviews the clinical results for these methods.

Purpose : To obtain reliable data on the extent of the brachytherapy practice in the United States by conducting a comprehensive survey of all facilities. Methods and Materials : The Clinical Research Committee of the AES surveyed all 1321 radiation oncology facilities identified in the Patterns of Care Study (PCS) of the American College of Radiology (ACR). Multiple mailings and follow-up were made to obtain a high response rate. Survey responders and nonresponders were compared using chi-square tests. Summary statistics were reported. Results : Of the 1321 facilities, 1054 responded (80%). Hospital-based and larger facilities had a statistically significant higher rate of response. Brachytherapy was being performed at 819 facilities (the median number of procedures = 21–50). Two hundred and two facilities did no brachytherapy. The common isotopes used were 137Cs (705 facilities), 192Ir (585 facilities), 125I (236 facilities), and 131I (194 facilities). The common brachytherapy techniques used were intacavitary (751 facilities), interstitial (536 facilities), intraluminal (310 facilities), and placques (148 facilities). Remote afterloaded brachytherapy was used at 205 centers as follows: high dose rate (HDR) (164), medium dose rate (MDR) (5), and low dose rate (LDR) (36). Computerized dosimetry was most commonly used (790 facilities), followed by Patterson-Parker (104 facilities) and Quimby (72 facilities). The common sites treated were cervix (701 facilities), endometrium (565 facilities), head and neck (354 facilities), and lung (344 facilities). Conclusions : data regarding brachytherapy practice has been obtained from a large percentage (80%) of all facilities in the United States. The majority (78–81%) of radiation oncology facilities perform brachytherapy; however, its use is restricted to gynecological implants in many of these centers. The results from this survey will be used to develop a pattern of care study and data registry in brachytherapy.

Objective The article explores the contemporary use of radiation therapy in the management of locally advanced prostate cancer. Methods The three main radiotherapeutic strategies that have been utilized in current clinical trials to optimize radiotherapy in the management of locally advanced prostate cancers are reviewed. These are to (1) increase the relative integral dose; (2) decrease the volume of tumor present; (3) optimize the biology. Results Results from the brachytherapy literature demonstrate that high doses may sterilize tumors more effectively. This concept has been taken into trials using conformal external beam radiation therapy. The Phase III trials conducted through the RTOG and in Canada are reviewed. These trials have demonstrated disease-free survival advantages of cytoreduction over conventional therapy alone. Neutron radiation therapy has also been evaluated in multicenter randomized studies, and the results there have demonstrated a superiority for neutron therapy over conventional photon therapy alone. Conclusion Although conventional photon radiation therapy may not be optimal inbulky prostate cancer, new techniques of optimizing radiation therapy by reducing the volume of tumor present or using techniques that give a biologically optimized dose or a physically increased dose may be of advantage in the future.

Objectives This article reviews the role of strontium-89 in the managementof prostate cancer, focusing on its kinetics and the clinical trial portfolio that is now available. Methods Strontium-89, a pure beta emitter with a half-life of 50 days, is taken up into bones, analogously to calcium. By strontium's favorable retention characteristics within the osteoclast/osteoblast reaction around bony metastases, it delivers a high dose of radiation to prostate cancer metastatic to bone, with a low dose to normal tissues. The results of clinical trials are presented. Results Phase II studies have demonstrated a 20% complete response rate to strontium-89 therapy in terms of pain. Phase III trials have demonstrated that isotopic strontium-89 is responsible for this effect, not molecular strontium. The TransCanadian Study has evaluated the use of strontium-89 as an adjuvant to local field radiation therapy and has demonstrated improvements in pain control and in duration of pain control. Optimization of strontium-89 therapy—for example, the combination of strontium and cisplatin therapy—may lead to an increase in subjective and objective response rates. Conclusions Strontium-89 is a good choice of therapy to palliate painful symptomatology in patients with endocrine refractory osseous disease secondary to prostate cancer.

From the Division of Urology, University of Colorado Health Sciences Center, Denver, Colorado; the Genitourinary Oncology Program and the Department of Urology, Northwestern University Medical School, Chicago, Illinois; the Department of Urology, Nijmegen University, Nijmegen, The Netherlands; Urologic Surgery, Memorial Sloan-Kettering Cancer Center and Cornell University Medical College, New York, New York; the Division of Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, Texas; the University of Colorado School of Pharmacy and the University of Colorado Cancer Center, Denver, Colorado; the Division of Nuclear Medicine, University of Kansas Medical Center, Kansas City, Kansas; the Department of Radiation Oncology, Harper Hospital, Detroit Medical Center and Wayne State University School of Medicine, Detroit, Michigan; and the Deparunent of Urology, Western Infirmary, Glasgow, Scotland

252Cf has been used as a brachytherapy source since the early 1970s. The dominant mechanism of interactions of 252Cf neutrons with tissue is elastic scattering. The scattered neutrons lose part of their energy, which is released as kinetic energy of the recoiling nuclei. By multiple scattering, neutrons lose their energy and eventually become thermalized (in energetic equilibrium with tissue atoms with an average energy of 0.025 eV) and do not play any role in radiotherapy. These thermal neutrons may interact with hydrogen nuclei or with nitrogen, but the cell killing effects by these reaction products are negligibly small compared to the elastic scattering by fast neutrons or by photons emitted by californium. Nonetheless, these thermal neutrons are still potentially usable for neutron capture therapy and can be used to enhance californium brachytherapy effects. Neutron capture therapy is a two-part therapy relying on the selective loading of tumor cells with compounds containing 10B or 157Gd and subsequent irradiation with thermal neutrons. To calculate neutron capture doses one has to know thermal neutron flux. This paper presents results of an experimental study of thermal neutron flux and calculations of boron neutron capture and gadolinium neutron capture doses in the vicinity of 252Cf sources.

Purpose: A large number of medical centers have recently instituted the use of High Dose-Rate Afterloading Brachytherapy (HDRAB). There is wide variation in treatment regimens, techniques, and dosimetry being used and there are no national standard protocols or guidelines for optimal therapy. Methods and Materials: The Clinical Research Committee (CRC) of the American Endocurietherapy Society (AES) met to formulate consensus guidelines for HDRAB in cervical, endometrial, and endobronchial tumors. Conclusion: Each center is encouraged to follow a consistent treatment policy in a controlled fashion with complete documentation of treatment parameters and outcome including efficacy and morbidity. Until further clinical data becomes available, the linear quadratic model can be used as a guideline to formulate a new HDR regimen exercising caution when changing from a Low Dose Rate (LDR) to a HDRAB regimen. The treatments should be fractionated as much as practical to minimize long term morbidity. As more clinical data becomes available, the guidelines will mature and be updated by the Clinical Research Committee of the AES.

Prostatic inhibin peptide (PIP), consisting of 94 amino-acid residues is synthesized and secreted by the prostate gland. Previous studies on immuno-histochemical localization of PIP in primary prostatic tumor and their metastasis, have documented the value of this peptide as a tumor marker for diagnosis of prostate cancer (PCa). The present study was undertaken to compare the expression of PIP with that of prostate specific antigen (PSA) and prostatic acid phosphatase (PAP) in androgen independent human PCa cell lines (PC-3, DU-145 and TSU-Prl) by immunoperoxidase technique. The results of the study indicated that the staining for PIP was more intense than that of PSA and PAP. The PSA staining was either weakly positive (PC-3) or totally absent (TSU-Prl and DU-145) while PAP staining was intense in PC-3 and moderate in the other two human cell lines. The intense staining observed for PIP in all of the androgen independent cell lines suggests that the synthesis and secretion of PIP is not primarily dependent on androgens. Furthermore, expression of these markers in Dunning rat cultured adenocarcinoma cell lines and tumors were studied. Positive staining for all three human tumor associated antigens (PIP, PSA and PAP) cross-reacting with the Dunning rat PCa cell lines and the tumors, suggest the suitability of this model for preclinical screening of various therapeutic agents.

Reports published in the English literature of clinical trials utilizing intravenous strontium 89 (89Sr) in the treatment of patients with prostatic adenocarcinoma metastatic to bone were reviewed. Correlation coefficients were calculated for increasing dose of 89Sr and complete pain relief and complete and partial pain relief. Statistically significant positive correlations were obtained for complete relief of pain. Positive correlations were also found between those patients who had at least partial pain relief (defined as at least a 50% reduction in analgesia requirement), but these did not reach significance. This analysis suggests that a dose response relationship may exist between the dosage of 89Sr administered, and complete relief of pain due to skeletal metastases. The optimal dosage of 89Sr in this clinical situation has not been established, and prospective, carefully executed and analyzed randomized trials will be required to test whether and to what extent dose intensity of 89Sr determines outcome independently of other factors.

Purpose: An important step in the development of 169 Yb as a new brachytherapy source is to determine its biological effectiveness relative to other commonly used radioisotopes. The purpose of this paper is to determine the relative biological effectiveness of 169 Yb, with respect to 60 Co, for a range of low dose rates. Method and Materials: The relative biological effectiveness of photon radiation from encapsulated 169 Yb was determined by exposing Chinese hamster ovary cells, in exponential growth, to graded doses of radiation from either 169 Yb or 60 Co. Clonogenic cell survival was determined for continuous low dose rates ranging from 6.5 cGy/hr to 52 cGy/hr. Results: The relative biological effectiveness of 169 Yb, with respect to 60 Co, was determined to be 1.2 ± 0.3 and did not vary significantly over the dose-rate range from 13 cGy/hr to 50 cGy/hr. An inverse dose-rate effect was observed, but only for 60 Co irradiation at 8.9 cGy/hr. Therefore, relative biological effectiveness values could not be determined reliably for dose rates less than 13 cGy/hr. Conclusions: We have established that 169 Yb is approximately 20% more effective than 60 Co in vitro . It is hoped that this study will guide the introduction of 169 Yb into clinical brachytherapy practice.

Background. Prostate brachytherapy represents one of the oldest techniques of using radiation therapy to treat prostate cancer. Over the past 10 years, there have been major changes in the types of prostate brachytherapy that can be performed with the introduction of new radioactive isotopes, new afterloading techniques, and an improved understanding of the radiobiology associated with differing dose rates. Methods. Prostate brachytherapy can be divided into temporary implantation using high activity sources such as iridium-192, or permanent brachytherapy using the interstitial implantation of iodine-125 or palladium-103 sources

The incidence of residual neoplastic cells on prostatic biopsy following conventional external beam radiotherapy is reported to range from 40–90%. As a result, it has been stated that current modalities of radiotherapy may carry an unacceptable local failure rate even in patients irradiated for low stage disease. In order to assess the potential benefits of threedimensional (3-D) treatment planning, an unselected, consecutive group of patients with localized adenocarcinoma of the prostate was evaluated. This study was designed to determine the frequency of residual cancer in the prostate two years following definitive external beam radiotherapy designed, using a 3-D planning system. Between February 1988 and February 1989, 30 consecutive patients with localized (Stage T1 -T3NxM0) adenocarcinoma of the prostate received definitive external beam radiotherapy. All treatment fields were designed with a computed tomography (CT)-based 3-D treatment planning system, resulting in a static conformal radiotherapy plan. The minimum dose delivered to the target volume, which included the prostate, periprostatic tissues, and a 1 cm margin, was between 65 and 69 cGy. Twenty-six patients had Stage T1, T2NxM0 primary tumors and four were T3NxM0. Two years following the completion of treatment, all patients underwent digital rectal examination, transrectal ultrasound examination of the prostate with multiple biopsies, bone scan, and serum prostate specific antigen (PSA) determinations. Residual prostate cancer was proven by biopsy in six of 30 patients (20%). Four of 26 (15%) with Stage T1 and T2 tumors had a positive biopsy. However, two of the four Stage T3 tumors had postradiation biopsies positive for cancer (50%). Only one patient with a positive biopsy had an abnormal rectal examination. Five of the eight patients with elevated serum PSA levels after two years had residual neoplasia identified on biopsy. One of six patients with an abnormal postradiation ultrasound had residual tumor. Only one of the 22 patients (5%) with a normal serum PSA at two years had a positive postradiation biopsy. In patients with localized prostate cancer, the use of 3-D static conformal radiotherapyfollowed by multiple ultrasound guided biopsies confirmed the efficacy of external beam radiotherapy in low stage disease. We believe that the low incidence of positive biopsies in this study resulted from the benefits of 3-D treatment planning as well as the fact that all patients were evaluated, whereas past studies have been in selected patient groups when suspicion of residual disease existed prior to biopsy. However, the 50% posttreatment positive biopsy rate in Stage T3 and T4 tumors underscores the unsatisfactory local control even with 3-D conformal radiotherapy. More aggressive treatment (e.g., neoadjuvant hormones, interstitial boost, hyperthermia, or dose escalation) may improve local control in these patients. It appears that routine postradiation biopsies may not be necessary in patients with normal serum PSA levels at two years following treatment. © 1993 Wiley-Liss, Inc.

It is believed that men diagnosed with prostate cancer and a low baseline serum testosterone (BST) may have more aggressive disease, and it is frequently recommended they forego testosterone replacement therapy. We used two large Phase III trials involving androgen deprivation therapy and external beam radiation therapy to assess the significance of a BST.All patients with a BST and complete data (n = 2,478) were included in this analysis and divided into four categories: "Very Low BST" (VLBST) ≤16.5th percentile of BST (≤248 ng/dL; n = 408); "Low BST" (LBST)16.5th percentile and ≤33rd percentile (248 ng/dL but ≤314 ng/dL; n = 415); "Average BST" (ABST)33rd percentile and ≤67th percentile (314-437 ng/dL; n = 845); and "High BST" (HBST)67th percentile (437 ng/dL; n = 810). Outcomes included overall survival, distant metastasis, biochemical failure, and cause-specific survival. All outcomes were adjusted for the following covariates: treatment arm, BST, age (70 vs. ≥70), prostate-specific antigen (PSA;10 vs. 10 ≤ PSA20 vs. 20 ≤), Gleason score (2-6 vs. 7 vs. 8-10); T stage (T1-T2 vs. T3-T4), and Karnofsky Performance Status (60-90 vs. 100).On multivariable analysis age, Gleason score, and PSA were independently associated with an increased risk of biochemical failure, distant metastasis and a reduced cause-specific and overall survival (p0.05), but BST was not.BST does not affect outcomes in men treated with external beam radiation therapy and androgen deprivation therapy for prostate cancer.

The palliative efficacy of strontium-89 chloride has been evaluated in a prospective double-blind crossover study comparing it with stable strontium as placebo in 32 patients with prostate cancer metastatic to bone. Response was assessed 5 weeks after each treatment. 26 patients were evaluable. Complete pain relief was only reported following strontium-89 injection. Statistical comparison between placebo and strontium-89 showed clear evidence of a therapeutic response to strontium-89 compared with only a limited placebo effect (P less than 0.01).

Purpose To determine whether adding 2 years of androgen-deprivation therapy (ADT) improved outcome for patients electively treated with ADT before and during radiation therapy (RT). Patients and Methods Prostate cancer patients with T2c-T4 prostate cancer with no extra pelvic lymph node involvement and prostate-specific antigen (PSA) less than 150 ng/mL were included. All patients received 4 months of goserelin and flutamide before and during RT. They were randomized to no further ADT (short-term ADT [STAD] + RT) or 24 months of goserelin (long-term ADT [LTAD] + RT). A total of 1,554 patients were entered. RT was 45 Gy to the pelvic nodes and 65 to 70 Gy to the prostate. Median follow-up of all survival patients is 11.31 and 11.27 years for the two arms. Results At 10 years, the LTAD + RT group showed significant improvement over the STAD + RT group for all end points except overall survival: disease-free survival (13.2% v 22.5%; P < .0001), disease-specific survival (83.9% v 88.7%; P = .0042), local progression (22.2% v 12.3%; P < .0001), distant metastasis (22.8% v 14.8%; P < .0001), biochemical failure (68.1% v 51.9%; P ≤ .0001), and overall survival (51.6% v 53.9%, P = .36). One subgroup analyzed consisted of all cancers with a Gleason score of 8 to 10 cancers. An overall survival difference was observed (31.9% v 45.1%; P = .0061), as well as in all other end points herein. Conclusion LTAD as delivered in this study for the treatment of locally advanced prostate cancer is superior to STAD for all end points except survival. A survival advantage for LTAD + RT in the treatment of locally advanced tumors with a Gleason score of 8 to 10 suggests that this should be the standard of treatment for these high-risk patients.