Decreased E-cadherin expression is associated with poor prognosis in patients with prostate cancer.

Decreased levels of the cell-cell adhesion molecule E-cadherin are associated with loss of differentiation in a number of human carcinomas. However, the value of E-cadherin as a prognostic marker in these cancers is largely undetermined. A previous study of E-cadherin levels in prostate cancer revealed that almost 50% of tumors examined had reduced or absent levels of this protein (Umbas et al., Cancer Res., 52: 5104-5109, 1992). To determine the potential prognostic significance of this finding, prostate cancer specimens from 89 patients were evaluated immunohistochemically for E-cadherin expression, and the results were related to histopathological grade, tumor stage, presence of metastases, and survival. As previously observed, a significant inverse correlation was found between E-cadherin expression and tumor grade. Importantly, we also found significant correlations between E-cadherin expression and tumor stage and overall survival. Sixty-three percent of the tumors that extended beyond the prostate capsule (T3-4) versus 33% of the tumors confined to the prostate (T1-2) had aberrant expression (chi 2 = 8.1, P < 0.005). Seventy-six percent of the primary tumors from patients that presented with metastases showed aberrant staining compared to 32% from patients without metastases (chi 2 = 14.9; P < 0.001). The life table analysis showed a significantly higher survival rate for patients with normal staining compared to patients with aberrant expression (chi 2 = 20.4, P < 0.001 by log rank test). Moreover, abnormal expression of E-cadherin correlated significantly with progression after radical prostatectomy (P < 0.005). These results suggest that E-cadherin expression can serve as a prognostic indicator for the biological potential of prostate cancer.

Intratumoral distribution of two consecutive injections of chimeric antibody G250 in primary renal cell carcinoma: implications for fractionated dose radioimmunotherapy.

Tumor uptake of the chimeric G250 (cG250) monoclonal antibody (mAb) in patients with primary renal cell carcinoma (RCC) is among the highest reported in solid tumors. However, as observed in other tumor types, the intratumoral distribution of the antibody is highly heterogeneous, which may limit the efficacy of radioimmunotherapy. A number of highly dynamic physiological factors have been postulated that may contribute to heterogeneous tumor uptake of antibodies. Their impact on tumor uptake of antibodies may vary from one tumor region to another as well as from one day to the next. Here, we report on a clinical study that was designed to investigate whether the pattern of mAb cG250 uptake within RCC tumors is altered with subsequent injections. Ten patients with a clinical diagnosis of primary RCC were studied. Nine days before surgery, patients received 125I-cG250 (5 mg of cG250, 50 microCi of 125I), followed by a second injection of 131I-cG250 (5 mg of cG250, 3.5 mCi of 131I) 4 days later. Postsurgery, the tumor was cut into (1-cm) thick slices. Slices were imaged on a gamma camera, and the slice with the most pronounced heterogeneity in 131I-cG250 distribution was selected and cut into 1-cm3 cubes. Each cube was analyzed for 121I-cG250 and 131I-cG250 uptake, and the 131I/125I ratio was determined. For each tumor slice, the distribution patterns of both isotopes were reconstructed and compared with each other. All tumors analyzed showed a heterogeneous distribution of both isotopes throughout the tumor slice; focal uptake in some areas of a tumor reached very high levels (up to 0.19% injected dose/g), whereas other tumorous areas of the same slice showed much lower uptake (as low as 0.0047% injected dose/g). Remarkably, in all tumors, the distribution pattern of both injections was identical: without exception, in all samples analyzed (n = 692), the uptake of 125I-cG250 was similar to 131I-cG250 uptake. Overall, the 131I/125I ratio was 1.64+/-0.31 (mean+/-SD). The constant 131I/125I ratios, observed in all tumor samples investigated, indicate that the tumor parameters governing cG250 mAb uptake were not altered significantly within the time period studied. In addition, the results of this study suggest that multiple radiolabeled antibody injections, administered within short time periods, will target the same areas within a tumor and, thus, will not solve the problem of heterogeneous tumor uptake of antibody.

Targeting of renal cell carcinoma with iodine-131-labeled chimeric monoclonal antibody G250.

PURPOSE: Pharmacokinetics, biodistribution, immunogenicity, and imaging characteristics of iodine 131 (131I)-labeled chimeric monoclonal antibody (mAb) G250 (cG250) were studied in patients with renal cell carcinoma (RCC) to determine the therapeutic potential of this antibody. PATIENTS AND METHODS: Sixteen patients with RCC received a single intravenous (IV) infusion of 6 mCi 131I-labeled cG250. Five protein dose levels were investigated (2 to 50 mg). Planar scintigraphic images were acquired, and normal tissue biopsies and tumor samples were obtained of surgery (7 days postinjection). The immunogenicity of cG250 was investigated using a sandwich enzyme-linked immunosorbent assay (ELISA) and dosimetric analysis was performed. RESULTS: In all patients with antigen-positive tumors (n = 13), the primary tumors and all known metastases were clearly visualized. Overall uptake, expressed as the percentage of the injected dose (%ID), in the primary tumors ranged from 2.4 to 9.0. Focally, 131I-cG250 uptake as high as 0.52% ID/g was observed. However, intratumoral uptake was highly heterogeneous. 131I-cG250 uptake in nontumorous tissues remained low. Dosimetric analysis showed that up to .48 Gy/mCi was guided to the primary tumors. Selected "hot areas" within these tumors received up to .72 Gy/mCi. A bone metastasis received .23 Gy/mCi and regional lymph node metastases received .20 Gy/mCi. Minimal human antichimeric antibody (HACA) levels were detected in two of 16 patients. CONCLUSION: 131I-cG250 tumor uptake is among the highest reported in clinical studies with antitumor antibodies in solid tumors. Since tumor-sterilizing levels may be guided to the tumor when high doses 131I-cG250 are administered (> 100 mCi) and cG250 appears to be immunosilent, cG250 is a promising vehicle for radioimmunotherapy in RCC.

Prognosis and treatment of T1G3 bladder tumours. A prognostic factor analysis of 121 patients. Dutch South Eastern Bladder Cancer Study Group.

Patients with T1G3 bladder cancer have a considerable risk for recurrence and/or progressive disease. Until now no consensus has been achieved on the optimal treatment. Within the Dutch South Eastern Bladder Cancer Study Group, 155 patients with a T1G3 bladder tumour were seen between 1983 and 1988. After review of histology, 121 could be evaluated and recurrence-free interval was studied with regard to prognostic factors. Prognostic factors such as sex, age, blood group, abnormalities on intravenous urography, pretreatment tumour configuration, number of tumours, number of locations involved in the bladder, voided urine cytology, results of random biopsies and mitotic index were evaluated, using a multivariate analysis with the Cox proportional hazard model. During the follow-up period, 70 (58%) patients had recurrent bladder cancer, and of these 30 (43%) had progression into invasive disease. Of the possible prognostic factors analysed, only multiplicity (P = 0.03) and the number of locations of the tumours (P = 0.03) were independent prognostic factors in relation to the risk of recurrence. The recurrence-free interval was influenced by the therapy. For T1G3 tumours, additional intravesical immunotherapy/chemotherapy or radiotherapy after transurethral resection (TUR) increased the recurrence-free interval significantly. Because most other parameters did not show additional prognostic value, the T1G3 tumours can be considered as homogeneous with regard to prognosis. Only multiplicity and the number of locations involved added to the prognostic significance of patients with these bladder tumours. In addition, it is advisable to give patients with T1G3 tumours additional treatment after the initial TUR.

Intratumoral nuclear morphologic heterogeneity in prostate cancer.

OBJECTIVES: Tumor heterogeneity can be measured by quantifying variance of nuclear characteristics by image analysis. Heterogeneity of cell nuclear features correlated with increased local progression in prostate cancer. In the present study, the influence of tumor heterogeneity on prostate-specific antigen (PSA) recurrence after radical retropubic prostatectomy was analyzed and tumor heterogeneity was compared in patients with and without neoadjuvant hormonal therapy. METHODS: Retrospectively, radical prostatectomy material of 44 patients without and 12 patients with neoadjuvant hormonal treatment with a postoperative follow-up of at least 4 years was studied. Each prostatectomy specimen was systematically embedded in paraffin, and each tumor area within the prostate was marked and analyzed by an image analysis system for 32 nuclear features comprising nuclear shape, size, DNA content, and chromatin pattern. Several clinical features were available: preoperative serum PSA, hemoglobin concentration, Karnofsky score, tumor stage, and Gleason score. RESULTS: Increased tumor heterogeneity, as expressed by differences in karyometric values between tumor areas in nuclear shape and chromatin pattern within the tumor, was significantly correlated with earlier PSA recurrence rate. As compared with nonpretreated patients, hormonally pretreated specimens showed smaller and less heterogeneous tumors. In particular, chromatin pattern heterogeneity was decreased in patients who underwent preoperative hormonal treatment compared with patients who were not pretreated. However, decreased heterogeneity was accompanied by a higher percentage of aneuploid areas per tumor in the pretreated patients. Cox regression analysis showed that karyometric determination of nuclear shape heterogeneity in combination with preoperative PSA level could predict time to PSA recurrence after radical prostatectomy in patients without hormonal pretreatment. CONCLUSIONS: Increase in karyometric tumor heterogeneity in nuclear shape and chromatin pattern was correlated with a shorter PSA recurrence-free interval after radical prostatectomy. Preoperative PSA and karyometric tumor heterogeneity were the best predictors of PSA recurrence in a multivariate analysis. Intratumoral heterogeneity was decreased in patients with prostate cancer who underwent neoadjuvant hormonal therapy.

Risk factors in carcinoma in situ of the urinary bladder. Dutch South East Cooperative Urological Group.

OBJECTIVES: In this article we describe the long-term follow-up of patients with carcinoma in situ (CIS) of the urinary bladder and examine whether the extent of CIS, the presence of associated papillary tumors, or the response to treatment influence the course of the disease. METHODS: Fifty-two patients with CIS of the bladder, treated in a randomized prospective study, are described. In 23 patients with concomitant papillary tumors all macroscopically visible lesions were completely resected transurethrally (TUR). CIS was histologically confirmed in all patients by biopsy, 29 of whom had primary CIS. The patients were treated with intravesical mitomycin, bacille Calmette-Guérin (BCG)-RIVM or BCG-Tice and followed regularly by urine cytology, cystoscopy, and biopsy. RESULTS: Complete response was achieved in 65% of the patients. Of these responders, 24% later had a recurrence of CIS or a superficial tumor and 18% had progressive disease (PD). In the nonresponding patients, progression occurred in 67%. In the whole group, PD was seen in 35% of the patients, and radical cystectomy was performed in 21%. The disease-related death rate was 13%. The risk for recurrence or PD was not higher in patients with more extensive CIS, defined as three or more positive biopsy results or when CIS was associated with papillary tumors compared to patients with one or two biopsy specimens positive for CIS or CIS alone. Nonresponding patients showed a significantly higher progression rate and cystectomy rate than responding patients (P = 0.0012 and 0.008, respectively). CONCLUSIONS: CIS of the bladder is a malignancy with a poor prognosis, especially in patients not responding after intravesical treatment. Early detection and adjuvant intravesical treatment after TUR of concomitant papillary tumors are required. In patients not responding after intravesical treatment, radical surgery is necessary before progression occurs. The number of biopsies positive for CIS, not the presence of concomitant superficial tumors, was an indicator for progression or recurrence.

Treatment in germ cell tumours: state of the art.

Although the majority of patients with disseminated germ cell tumours can be cured with cisplatin-based chemotherapy, mortality is still up to 20%. Several prognostic factors have been identified to differentiate between patients with a good, intermediate or poor prognosis. In this review we discuss the recent chemotherapy trials, which were designed to reduce toxicity in good-prognosis patients and to improve efficacy in intermediate- and poor-prognosis patients. In good-prognosis patients it is obvious that the omission of bleomycin and the replacement of cisplatin by carboplatin has no place in first-line standard treatment. The reduction of four standard courses of bleomycin, etoposide and cisplatin (BEP) to three is shown possible in one study, but a confirmatory study is currently ongoing in the EORTC. In intermediate- and poor-prognosis patients, the use of new agents or alternating regimens (with or without shortened intervals) did, by now, not improve final outcome. The role of high-dose chemotherapy remains to be determined. Against this background, four courses of standard-dose BEP should still be considered treatment of first choice in the majority of patients with disseminated germ cell tumours. Furthermore, the policy in clinical stage I disease has been reviewed. In clinical stage I seminoma patients the policy is to apply adjuvant radiotherapy, while the strategy in patients with non-seminomatous tumours (surveillance, retroperitoneal lymph node dissection or adjuvant chemotherapy in high-risk patients) depends highly on the local situation, such as the operating skills of the urologist, and on the possibilities for tight follow-up. Of patients with true resistance for up-front BEP chemotherapy 90% will normally die. In patients who achieve a complete response on first-line chemotherapy, but relapse thereafter 30% will have no evidence of disease with second-line chemotherapy (VIP). In this group of patients results with high-dose chemotherapy seem promising, but its value should preferentially be determined in either a randomized fashion or by long-term follow-up from a large group of patients according to a similar protocol. The use of post-chemotherapy surgery is an essential part of management for metastatic non-seminomatous germ cell tumours, while the majority of residual masses in pure seminoma will disappear spontaneously, and frequent follow-up is recommended instead of surgical intervention.

In vivo proton MR spectroscopy reveals altered metabolite content in malignant prostate tissue.

BACKGROUND: Recently the potential of magnetic resonance (MR) methods for non-invasive diagnosis and therapy evaluation of prostate cancer has improved substantially. In this study proton MR spectroscopy (1H MRS) was explored for the detection of cancer in the prostate. PATIENTS AND METHODS: Employing an endorectal probe localized 1H MRS and contrast enhanced MR imaging was performed on the prostate of healthy volunteers and of patients with benign prostatic hyperplasia (BPH) and/or prostate cancer (PCa). RESULTS: 1H MR spectra of the human prostate showed major signals for citrate, creatine and choline compounds. For cancer tissue the average citrate/choline signal ratio was significantly lower than for BPH and non-cancerous peripheral and central zone tissue, but individual ratios overlapped with ratios for normal central zone and BPH tissue. Low citrate/choline ratios in tumour tissue correspond with early MR contrast enhancement. CONCLUSIONS: 1H MRS has potential for non-invasive detection and follow-up of tumours in the prostate.

Effects of high-energy shock waves combined with biological response modifiers in different human kidney cancer xenografts.

We have studied the effects of high-energy shock waves (HESW) alone or in combination with biological response modifiers on the growth of five human kidney cancer xenografts in mice. Exposure of the tumors to three sessions of 800 shock waves every 48 hours with 18.4 kV, 37.5 MPa, on the commercially available Lithostar resulted in a temporary growth delay. The sensitivity for HESW was related to the doubling time of the tumor. Several days after stopping the HESW administration, the tumors regained their original growth potential with the same doubling time. The systemic application of Tumor Necrosis Factor-alpha (TNF-alpha, 500 ng/g body weight, 5 times/week) and/or Interferon-alpha (IFN-alpha, 5.0 ng/g body weight, 3 times/week) subcutaneously around the tumor also had a limited effect on the growth of these established tumors (60-80 mm3). The combination of HESW with TNF-alpha and IFN-alpha resulted in an almost complete cessation of tumor growth in the NU-1 human kidney xenograft and had an additive antitumor effect in the NU-3. Synergism was also seen in the NU-1 and NU-3 with the combination of HESW and TNF-alpha, while the combination with IFN-alpha had only a limited effect on tumor growth. So TNF-alpha was the active agent, that enhanced the antiproliferative effects of shock waves. In the NC-65 tumor (same doubling time as the NU-1 and NU-3, but less well vascularized), the antiproliferative effect of HESW was not potentiated by TNF-alpha.(ABSTRACT TRUNCATED AT 250 WORDS)

The influence of high-energy shock waves on the development of metastases.

The hypothesis that exposure of a solid tumor to high-energy shock waves (HESW) could lead to an increase of metastases was investigated in an animal model. The highly metastatic AT-6 Dunning R3327 rat prostate cancer subline was implanted in the hind limb of a Fisher-Copenhagen rat and was exposed to 6000 shock waves delivered by an experimental lithotripter, or sham-treated, as soon as the tumor had reached a volume of 175-225 mm3. The tumor-bearing leg was amputated 24 h later and the number of metastases was examined 12 weeks thereafter at autopsy. Metastases were seen in 82% of the animals exposed to HESW and in 25% of the sham-treated animals. There was no significant difference in weight of the lungs that contained metastases, between sham and treated animals. These results were confirmed in a second experiment. We conclude that the metastatic spread of tumors with a high metastatic potential may be enhanced by shock-wave exposure.

Early metabolic response to high energy shock waves in a human tumor kidney xenograft monitored by 31P magnetic resonance spectroscopy.

The effects of electromagnetically generated high-energy shock waves (HESW, Siemens Lithostar) on the phosphate metabolite levels of the NU-1 human kidney cancer xenograft implanted under the skin of the hind limb of nude mice were monitored by 31P magnetic resonance spectroscopy (MRS). Administration of 200 and 800 HESW (18.1 kV, P(+) = 37.5 MPa, P(-) = 5.2 MPa, tr = 30-120 nsec, tw = 340 nsec, freq. = 1.25 Hz), focused on the tumor centre, resulted in an immediate tumor decline; 2 h after exposure to the HESW, the high-energy phosphate resonances had decreased drastically. This decline in energy rich molecules was accompanied by a concomitant increase in the inorganic phosphate resonance and a decrease in pH of the tumor. During the following period, a dose-time dependent recovery of the original high-energy phosphate resonance intensities was observed. These changes are qualitatively similar to those produced by ischemic inhibition of energy metabolism and are correlated with early histological features like vascular disruption, stasis within capillaries, and focal thrombosis. These results demonstrate that experimental HESW treatment of the NU-1 kidney tumor is effective in provoking a temporary reduction of both high-energy phosphate metabolism and tissue pH of the tumor. The data presented here strongly suggest that these effects are predominantly indirect by affecting tumor vascularity. Overall, this study shows that MRS is a powerful technique for longitudinal investigations of HESW-induced effects and can provide information about its mode of action.

Biological effects of high energy shock waves in mouse skeletal muscle: correlation between 31P magnetic resonance spectroscopic and microscopic alterations.

To investigate the in vivo effects of electromagnetically generated high energy shock waves (HESW) on skeletal muscle, we used in vivo 31P nuclear magnetic resonance (NMR) spectroscopy (MRS) measurements and correlated the results with microscopical studies. Mouse skeletal muscle (calf muscle) was exposed to 200 or 800 HESW (Pmax: 37.5 MPa, Pmin: 5.2 MPa, tr: 30-120 ns, tw: 340 ns, frequency: 1.25 Hz). In the 31P MRS spectra, transient alterations were observed. A prominent increase of inorganic phosphate (Pi) peaks was found, as well as the appearance of Pi with different chemical shifts, reflecting the presence of different pH values (5.4-7.1) in cellular or tissue compartments. Within 20-96 h after exposure, pH values and Pi levels returned to normal. The changes were more pronounced in the animals treated with 800 HESW as compared to 200 HESW. Light and electron microscopy demonstrated focal degenerations of muscle fibers. This process consisted of disorganization of myofilaments and structural changes in sarcoplasmic organelles and was progressive in time. The (ultra)structural changes were not present in all myofibers (i.e., between affected degenerating fibers unaffected intact fibers were seen). Several ultrastructural abnormalities were also found in capillaries even up to severe dilatation and disruption, as well as in the peripheral nerves. The degeneration of the preexisting myofibers was predominantly confined to type 1 fibers and was followed by a regeneration of the muscle tissue by proliferation of myoblasts. A notable amount of myotubes still showed vacuolization. We conclude that in vivo HESW exposure of skeletal muscle tissue results in a degeneration of myofibers. The cellular effects are present in foci and associated with changes in the 31P NMR spectra. The NMR spectroscopy technique provides us with a noninvasive method to evaluate in a longitudinal way the biological effects of HESW.

The effects of successive high-energy shock-wave tumor administration on tumor blood flow.

The effects of repeated high-energy shock wave (HESW) tumor administration on tumor blood flow (TBF) were studied in NU-1 human kidney cancer xenografts. Deuteriated water was used as a magnetic resonance spectroscopic detectable tracer for measuring tumor blood flow. Tumors were exposed twice to 800 electromagnetically generated HESW, with a 24-h interval or sham exposed. No changes in TBF occurred after sham exposure to HESW. TBF levels 2 h after the first and second HESW application were, respectively, 46% and 37% lower than the mean preexposure TBF value and returned to normal levels within 16 h. There was statistically no difference found between the effects on tumor blood flow after the first and second HESW exposure. These observations are in agreement with earlier studies and provide a rationale to shorten the time interval between HESW monotreatments to 2 to 3 h.

[What are the contributions of experimental studies to the diagnosis and therapy of urological tumors?]. / Wat zijn de bijdragen van experimenteel onderzoek voor de diagnostiek en therapie van urologische tumoren.

The contribution of experimental research in the diagnostics and therapy of urological malignancies is based on different approaches. One of the most important techniques is the development of tumor markers which can predict progression of the tumor. These markers can be detected by molecular biological techniques, by immunohistochemistry or by other quantification techniques such as morphometry and flowcytometry. New indications for progression are initially researched in tumor model systems. The in vitro systems are extremely well suited for those fundamental studies especially molecular biological analysers, because the tumors in these systems are homogeneously composed and lack the heterogeneity of in vivo tumors. The methodology of markers developed by such techniques have subsequently been tested on human tumor material of which the evolution was known (retrospective analyses). Animal models can also contribute to fundamental research in urological tumors, more particularly to evaluate the efficacy of new experimental therapeutic approaches. Therapies with proven effect in the animal models have to be tested subsequently in humans and if effective, have to be investigated further to improve the dose- and/or route of administration. One result of such research is the use of immunotherapeutics in metastatic renal cell carcinoma. Basic research in oncological urology may in this way contribute to the further improvement of the diagnosis and treatment of urological malignancies.

[Gynecomastia in testicular tumors]. / Gynaecomastie bij testistumoren.

The incidence of gynaecomastia among 224 patients treated between 1981 and 1989 for testicular cancer was studied retrospectively. Gynaecomastia was present as an initial symptom in 25 (11%) patients and developed after chemotherapy or radiotherapy in 19 (9%) patients. Gynaecomastia was mainly seen in patients with high tumour stages. It therefore points to an unfavourable prognosis.

[Laparoscopic pelvic lymph node dissection valuable in the staging of clinically localized prostate carcinoma]. / Laparoscopische pelvine lymfeklierdissectie goed bruikbaar voor de stadiëring van klinisch gelokaliseerd prostaatcarcinoom.

OBJECTIVE: To assess the value of laparoscopic lymph node dissection of the obturator fossa in patients with prostate carcinoma with high risk of lymph node metastases. DESIGN: Prospective descriptive study. SETTING: Department of Urology, University Hospital Nijmegen, the Netherlands. METHOD: Prior to curative therapy for prostate carcinoma a bilateral laparoscopic pelvic lymph node dissection was performed in 25 patients, with a high risk of lymph node metastases on the basis of tumour size, tumour grade or serum prostate specific antigen. RESULTS: In 52% (13/25) of the patients lymph node metastases were found. Once a laparotomy was performed for an arterial bleeding. A mean of 11.6 lymph nodes were removed during bilateral dissection of the obturator fossa. Three quarter of the patients were discharged one day postoperatively. CONCLUSION: A laparoscopic lymph node dissection is a valuable tool for the evaluation of pelvic lymph nodes in patients with a clinically localised prostate carcinoma and a high risk of lymph node metastases.

[Benign prostatic hyperplasia; recommendations for transmural care. Working Group, Dutch College of General Practitioners and Netherlands College of Urologists]. / Benigne prostaathyperplasie; aanbevelingen voor transmurale zorg.

Both the Netherlands College of Urologists (NVU) and the Dutch General Practice College (NHG) in recent years published guidelines for the management of benign hypertrophy of the prostate (BPH). The two differ in a number of respects and are not always consistent. The differences between the GP's and urologists' guidelines are mostly to be attributed to the difference in the patient populations visiting the GP and the urologist, respectively. In order to arrive a better adjustment concerning BPH patients between general practice and specialists, a team composed of NVU and NHG has drawn up 'Recommendations for transmural care'. These recommendations concern four subjects: diagnosis of micturition abnormalities, indication for examination of cancer of the prostate, drug treatment, indications for referring and re-referring of patients with micturition problems.

Effect of a nutritional supplement containing vitamin E, selenium, vitamin c and coenzyme Q10 on serum PSA in patients with hormonally untreated carcinoma of the prostate: a randomised placebo-controlled study.

OBJECTIVE: To assess the effect of a nutritional supplement containing vitamin E, selenium, vitamin C and coenzyme Q10 on changes in serum levels of PSA in patients with hormonally untreated carcinoma of the prostate and rising serum PSA levels. METHODS: Eighty patients were randomised to receive a daily supplement with either vitamin E, selenium, vitamin C, coenzyme Q10 (intervention group) or placebo over 21 weeks. Serum levels of PSA were assessed at baseline (-2, -1, 0 weeks) and after 6, 13, 19, 20 and 21 weeks. Mean changes in log serum level of PSA, testosterone, dihydrotestosterone, luteinizing hormone and sex hormone binding globulin over 21 weeks between the verum and the placebo group were compared by analysis of covariance. RESULTS: Seventy patients completed the study (36 verum; 34 placebo). Compliance was >90% in all patients. In the intervention group, plasma levels of vitamin E, selenium and coenzyme Q10 increased significantly over the 21 weeks study period. No significant differences in serum levels of PSA, testosterone, dihydrotestosterone, luteinizing hormone or sex hormone binding globulin (p>0.2) were observed between the intervention and control group. CONCLUSION: Our results indicate that supplementation of a combination of vitamin E, selenium, vitamin C and coenzyme-Q10 does not affect serum level of PSA or hormone levels in patients with hormonally untreated carcinoma of the prostate.

Update of hormonal treatment in cancer of the prostate.

Prostate carcinomas are heterogeneous tumors composed of hormone sensitive and hormone insensitive cells. Although all androgens have an effect on prostatic cells, it is believed that dihydrotestosterone (DHT) is the active metabolite primarily utilized by prostatic cancer cells for growth and division. Hormonal therapies are therefore designed to lower tissue levels of DHT or prevent its binding to receptors on prostatic cancer cells. The Veterans Administration Cooperative studies in the 1960s and 1970s laid the groundwork for the use and timing of hormonal therapy. Until recently orchiectomy and estrogens were the two main alternatives, but new compounds such as luteinizing hormone releasing hormone analogs and antiandrogens have shown to be as effective and less toxic than estrogens. Today, important controversies concerning the selection of the best primary treatment and the timing of initiating the hormonal therapy still exist. Second line hormonal strategies are used, but they still have to prove their impact on overall survival.