J. H. M. Blom

Radical nephrectomy with and without lymph-node dissection: final results of European Organization for Research and Treatment of Cancer (EORTC) randomized phase 3 trial 30881.

BACKGROUND Until now the therapeutic value of lymphadenectomy for renal-cell carcinoma has remained controversial. Several studies attempting to solve this controversy have been published, but none of them were set up as prospective randomized trials. OBJECTIVE To assess whether a complete lymph-node dissection in conjunction with a radical nephrectomy for renal-cell cancer is more effective than a radical nephrectomy alone. DESIGN, SETTING, AND PARTICIPANTS In 1988, the European Organization for Research and Treatment of Cancer (EORTC) Genitourinary Group started a randomized phase 3 trial comparing radical nephrectomy with a complete lymphadenectomy to radical nephrectomy alone. After the renal-cell carcinoma was judged to be N0M0 and resectable, patients were randomly selected prior to surgery to undergo either a radical nephrectomy with a complete lymph-node dissection or to undergo a radical nephrectomy alone. Postoperatively all patients were followed for progression of disease and mortality. INTERVENTION All patients underwent a radical nephrectomy with or without a complete lymph-node dissection. MEASUREMENTS All patients were postoperatively evaluated for time-to-progression, overall survival, and progression-free survival. Time-to-event curves were estimated based on the Kaplan-Meier method and compared using a two-sided log-rank test. RESULTS AND LIMITATIONS Of the 772 patients selected for randomization, 40 were not eligible for the study. 383 patients were randomly selected to receive a complete lymph-node dissection together with a radical nephrectomy, and 389 patients were randomly selected to undergo a radical nephrectomy alone. The complication rate did not differ significantly between the two groups. Complete lymph-node dissections in 346 patients revealed an absence of lymph-node metastases in 332 patients. The study revealed no significant differences in overall survival, time to progression of disease, or progression-free survival between the two study groups. CONCLUSIONS This study shows that, after proper preoperative staging, the incidence of unsuspected lymph-node metastases is low (4.0%) and that, notwithstanding a possible relationship to this low incidence rate, no survival advantage of a complete lymph-node dissection in conjunction with a radical nephrectomy could be demonstrated.

Diagnosis and Management of Seminal Vesicle Cysts Associated with Ipsilateral Renal Agenesis: A Pooled Analysis of 52 Cases

Objective: Seminal vesicle cysts combined with ipsilateral renal agenesis represent a rare urological anomaly. We searched the literature to review the clinical presentation, diagnosis and therapeutic treatment options of this anomaly. Methods: A pooled analysis was performed of 52 cases of seminal vesicle cysts combined with ipsilateral renal agenesis, including our own observation. The evaluation included: patient age at diagnosis, race, laterality (R/L), presence of ureteral remnant in the cyst, presenting symptoms, diagnostic examinations, treatment and outcome. Results: The mean age at diagnosis was 30.2 years. The majority presented in the 2nd, 3rd and 4th decade of their lives. Only 2 patients (4%) were of African origin, all others were Caucasians. The distribution R:L was 2:1. Ureteral remnants were present in 14 patients (27%). The most common symptoms were: dysuria (37%), frequency (33%), perineal pain (29%), epididymitis (27%), pain following ejaculation (21%) and scrotal pain (13%). Infertility was found in 9 patients (17%). The cyst was palpable by digital rectal examination in 79%. All patients underwent intravenous urography, and 88% underwent cystoscopy. Other frequently performed investigations are: ultrasonography (27%), CT scanning (27%), vasovesiculography (46%) and urethrocystography (23%). The final treatment was open surgery in 74%, aspiration in 6%, transurethral deroofing of the cyst in 6% and spontaneous rupture in 4%. In 6% no treatment was given and in 4% the treatment is unknown. All patients were free of symptoms after open exploration. The success rates after transurethral deroofing and aspiration were 75 and 30% respectively. Conclusion: Seminal vesicle cysts combined with ipsilateral renal agenesis are a rare urological anomaly, occurring in men in the 2nd to 4th decade of their life. They present with symptoms of bladder irritation and obstruction and with pain in the perineum and scrotum. Epididymitis is frequently found. The diagnostic work-up consists of a digital rectal examination, transrectal and abdominal ultrasonography, CT scan and a cystoscopy. Open surgery and transurethral deroofing of the cyst give excellent results (100 and 75% cure respectively). Aspiration of the cyst should only be used for diagnostic purposes.

Treatment of Benign Prostatic Hyperplasia by Androgen Deprivation: Effects on Prostate Size and Urodynamic Parameters

The possible effect of medical androgen deprivation in the treatment of benign prostatic hyperplasia has been studied in 12 patients. Six patients received the luteinizing hormone-releasing hormone agonist buserelin and 6 others received the antiandrogen cyproterone acetate. The treatment resulted in an average decrease in prostatic size of 29 per cent after 12 weeks as measured by ultrasonography. This decrease led to an increase in peak urinary flow rate, a reduction in residual urine volume and a decrease in daytime voiding frequency. However, it caused no decrease in urethral resistance but only an increase in the bladder contraction strength. After discontinuation of the treatment the prostates showed regrowth to the initial sizes within 6 to 36 weeks. The urodynamic changes were reversed as well. Although statistically significant, the urodynamic changes were minimal from a clinical viewpoint and did not lead to an unobstructed state after 12 weeks of treatment. For this reason the clinical indication for use of medical androgen deprivation in benign prostatic hyperplasia patients will remain limited for the time being.

Deoxyribonucleic acid ploidy of core biopsies and metastatic lymph nodes of prostate cancer patients: Impact on time to progression

We studied 98 patients with locally confined but lymph node positive prostatic cancer (1 stage T1, 29 stage T2, 55 stage T3 and 2 stage T4) who were not treated by radical prostatectomy. A retrospective analysis was done of deoxyribonucleic acid (DNA) ploidy of pretreatment core biopsies of the primary tumor and lymph node metastases. While DNA ploidy has been shown to be an important prognostic factor if applied to radical prostatectomy specimens, core biopsy specimens and nodal metastases have rarely been studied. Of the 98 patients 87 were evaluable for DNA ploidy: 45 (52%) had diploid, 13 (15%) had tetraploid and 29 (33%) had aneuploid tumors. The ploidy of the primary tumor and of the lymph node metastases correlated significantly with the rate of progression and interval to progression. Also, significant correlations were noted between the percentages of cells in the S phase or S plus G2 phases of the cell cycle and interval to progression. Most patients in this study are part of the European Organization for Research and Treatment of Cancer protocol 30846, a prospective randomized study of early versus delayed treatment in lymph node positive, otherwise locally confined prostate cancer. This study is ongoing. Early endocrine treatment was associated with a significantly longer interval to progression. In a Cox regression analysis of the prognostic factors involved in this study, early endocrine treatment was more important than ploidy or proliferation patterns. Stage (T category) and histopathological grade did not show a correlation with progression. Followup is still too short and the numbers of patients are too small for relevant subgroup analysis. DNA ploidy measurement by flow cytometry on archival (paraffin embedded) core biopsy and lymph node material is possible, and produces meaningful results in predicting the prognosis of prostatic cancer. Since this information can be made available before treatment decisions, its exact value in the management of locally confined prostate cancer can be determined.

Erection Problems in Medical Practice: Differential Diagnosis with Relatively Simple Method

Functional sexual potency can be assumed when penile erection occurs during visual erotic stimulation, and to a lesser degree with normal nocturnal penile tumescence. Erection, increase in circumference as well as rigidity, can be measured with a simple device consisting of a calibrated felt band with a sliding collar fastened to 1 end. Subjects were 58 consecutive patients, mainly from a urology outpatient department, with erection problems and 67 healthy control men. Changes in penile circumference were measured during viewing of an erotic videotape and during sleep. Functional sexual potency, at least partially, was presumed to exist in 41 patients (71%), many of whom had a somatic pathological condition that might easily have been believed to be the cause of the erectile dysfunction. During the latter half of the study nocturnal penile tumescence also was measured. This group included 7 patients who did not respond to the visual stimuli, 5 of whom had normal nocturnal penile tumescence. We conclude that the erection meter, in conjunction with an erotic video test and nocturnal penile tumescence measurements, is a useful and simple device in the differential diagnosis of erectile difficulties in men. This is true especially when elaborate sleep laboratory facilities and neurophysiological equipment are not available.

Dietary intervention in prostate cancer patients: PSA response in a randomized double-blind placebo-controlled study

The objective of this study was to show or to exclude an effect of dietary supplement on rising prostate‐specific antigen (PSA) levels. We have studied the effect of a dietary supplement (verum, administered for 6 weeks) containing plant estrogens, antioxidants, including carotenoids, selenium and other putative prostate cancer inhibiting substances in a randomized placebo‐controlled double‐blind crossover study in 37 hormonally untreated men with prostate cancer and increasing PSA levels. Outcome measures were changes in the rates of change of serum concentrations of total and free PSA and changes in male sex hormone levels. Male sex hormone levels were significantly lower during the verum phase (DHT: −0.11 nmol/L, p = 0.005; testosterone: −1 nmol/L, p = 0.02). Total PSA doubling time was unaffected. Free PSA, which increased during the placebo phase (average doubling time of 68 weeks), decreased during the verum period (average half‐life of 13 weeks; p = 0.02). In those men in whom the free androgen index decreased (21 out of 32), a significant decrease in the slopes of both total and free PSA was observed (p = 0.04). Overall total PSA doubling times did not increase significantly during verum. However, the study demonstrates that this dietary intervention reduces DHT and testosterone levels and increases free PSA doubling time (and total PSA doubling time in a relevant subgroup). If future studies confirm that these observations translate into a slowing of disease progression, a dietary intervention may become an attractive option for prostate cancer treatment and prevention.

Transrectal Ultrasonography in the Followup of Prostatic Carcinoma Patients

Prostatic volume was determined by transrectal ultrasonography before and after castration in 13 patients, and after radiotherapy in 24. Measurements were done after 1, 2 and 3 months, and subsequently at 3-month intervals. Significant volume reductions occurred in the castration and radiation groups within 3 months. The decrease in prostatic volume was significantly more pronounced in the castration group during the entire study (p less than or equal to 0.01). Patients with enlargement of the prostate predominantly owing to benign prostatic hypertrophy also had a decrease in volume. No increase in prostatic volume after initial reduction was encountered for up to 9 months. In several cases progression of metastases occurred with no increase in the volume of the primary tumor. Followup may be too short to encounter local recurrence after radiotherapy or hormone-independent growth after castration. Proctitis after radiotherapy created artifacts that probably led to inaccurate measurements with ultrasonography. The technique provides a new, accurate parameter for followup of conservatively treated prostatic cancer patients. The clinical importance of the technique still remains to be determined.

Problems in grading of prostatic carcinoma: interobserver reproducibility of five different grading systems

SummaryIn order to investigate the reproducibility of grading systems for prostatic carcinoma currently in use, a comparative histological grading study was done. These studies were carried out on tissue sections from radical prostatectomy specimens (N=50) stained with hematoxylin and eosin. Five pathologists with varying professional experience participated in the study, using five different grading systems: those of Broders, Brawn, Gleason (for statistical compilation the modified version), Mostofi, and a modified Mostofi grading method recently described by Schroeder and Mostofi. Weighted kappa coefficients ranged from 0.21 to 0.52. None of the systems investigated demonstrated a high degree of reproducibility (k>0.70). Reproducibility of the systems described by Broders and Brawn was reasonably good (k=0.52 and 0.41, respectively). With the modified Gleason method (rearrangement of Gleason scores into 3 grades), a considerable difference was noted between the numerical agreement score (among at least 3 observers) and the measured kappa value (100% and 0.30, respectively). The methods described by Mostofi and Schroeder-Mostofi revealed only limited reproducibility (k=0.21 and 0.34, respectively).

Morphometrically estimated variation in nuclear size

SummaryAt present there are several grading systems for prostatic carcinoma. Most are difficult to reproduce. An objective method of grading seems to be necessary and could make comparisons between various groups of patients easier and grading more reliable.In the present study morphometrically estimated nuclear size and variation in nuclear size are matched with the survival rates of 207 patients who underwent total perineal prostatetomy for cancer. On the basis of morphometrically estimated variation in nuclear size the patients could be divided into two groups with significantly differing survival rates. In this way it was possible to split the group of patients with grade 2 carcinoma (Mostofis grading system) into two groups of patients with significantly different survival rates. The survival rates in these two groups did not differ significantly from those in the patients with Grade 1 and Grade 3 tumors respectively.The results are discussed in the light of the recent literature on the subject. Morphometry seems to be a valuable tool in grading prostatic cancer.

Incidental carcinoma of the prostate treated by total prostatectomy

SummaryA retrospective study of 55 patients with incidental prostatic carcinoma with long term follow-up is presented. All patients were treated with total perineal prostatectomy, 43 received some form of endocrine treatment after the initial diagnosis was made. In order to contribute to the establishment of low and high risk groups which do not or do require agressive treatment, a careful histological analysis of the 39 patients was carried out on whom total prostatectomy slides with tumor were available. The amount of tumor, grade and parameters commonly used to establish grading were determined and correlated with corrected survival. The findings indicate that a small amount of tumor, grade 1, the presence of small, intermediate or large glands (but not cribriform and/or solid tumor) and the presence of slight but not moderate or marked variation in size and shape of the nucleus are strong predictors of not dying from prostatic carcinoma. There is agreement with the literature, where similar groups of patients not further treated after the initial diagnosis had been established showed a comparably low number of progressions. It is concluded that small, well differentiated prostatic carcinomas (category T0pT1NxM0G1, stage A1) do not require an aggressive diagnostic work-up or further treatment. A group of 11 patients (27%) showed more extensive but well differentiated tumors. Only two of these patients died of prostatic carcinoma. The natural history of this entity is not sufficiently known to make definite treatment decisions. Staging, radical prostatectomy, radiotherapy or deferred treatment may be indicated. Grade 3 carcinoma or the presence of cribriform and/or solid tumor were strong predictors of progression and death from prostatic carcinoma. Seven of 14 patients with these characteristics died of their disease. It is concluded that at least the experience in this series does not show radical prostatectomy to be an optimal treatment in this group of patients. Smaller rates of progression are however described in the literature. Endocrine management does not seem to have any beneficial effect, reports on radiotherapy are scarce. The optimal treatment for this group of patients with a high risk of dying from their tumor and a significantly shortened overall survival is not known.