Acta Oncologica

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Prostatic Cancer: An overview L. Denis & C. Mahler To cite this article: L. Denis & C. Mahler (1990) Prostatic Cancer: An overview, Acta Oncologica, 29:5, 665-677, DOI: 10.3109/02841869009090072 To link to this article: https://doi.org/10.3109/02841869009090072

Published online: 08 Jul 2009.

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Reviews in Oncology 3 (1990) 2 (in Acra Oncologica Vol. 29, Fasc. 5.) FROM THE DEPARTMENT OF UROLOGY-ENDOCRINOLOGY, ALGEMEEN ZIEKENHUIS, MIDDELHEIM, ANTWERP, BELGIUM.

PROSTATIC CANCER An overview L. DENISand C. MAHLER

Abstract Reliable study results are scarce in prostate cancer for several reasons. The treated tumors represent a wide variety of natural history and therapeutic response. One assumes to select ‘soft’ or minimally toxic treatment for patients with good prognostic factors while aggressive treatment is reserved for infaust prognosis. Stage, grade and prognostic factors may influence the indication and choice of treatment. Better treatment selection will depend on the outcome of actual ongoing randomized trials, the development of new drugs or existing drugs in new indications and, above all, basic studies on the growth potential and invasiveness of the prostate cancer cell. Defining the correct treatment for the right cancer in the right patient is our clinical challenge for the next decade. Key words: Prostatic cancer, survival, biologic markers, grading, staging, treatment.

Cancer of the prostate has in recent years become the second most frequent male cancer reported in most industrial nations of Europe and North America and in some of these countries even the most frequent. There are two explanations for this fact. First, the peak incidence of prostate cancer occurs at the median age of 70 years and we have fortunately a greater number of men in this age range than ever before. Second, new medical technology contributes to detection of prostate cancer in earlier stages of disease. This early detection is often difficult due to coexisting pathology as benign prostatic hyperplasia and chronic prostatitis in an age group where unrelated mortality by cardio-vascular diseases makes the clinical relevance of early prostatic cancer complex. We need a European survey of prostatic cancer similar to the National USA Survey organized by the American College of Surgeons (1) to provide us with data on the occurrence of the different clinical stages at the time of diagnosis.

The Task Force Programme from the European School of Oncology revealed that information on prostatic cancer was widely disseminated but also that large national and regional differences in health delivery existed (2). It is hoped that the result of consensus conferences organized by the European Organization for Research and Treatment of Cancer (EORTC) under the auspices of the Europe Against Cancer programmes may resolve some of controversies regarding prostate cancer management. Natural history

The problem of the pathological complexity of the prostate is illustrated by the textbooks of urology in the beginning of this century where no distinction is made between benign and malignant hypertrophy. Advances in pathological sciences cleared these misconceptions rapidly and audacious surgeons such as Hugh Young pioneered the systematic evaluation and surgical excision of the carcinomatous glands by the perineal route. Later autopsy studies established the prevalent existence of incidental prostate cancers in about half of the examined prostates in men over 50 years of age while incidence statistics showed that less than 1% of these cancers developed into clinical disease. Jewett pursuing the surgical cure of early diagnosed prostatic cancer noted that most of these incidental lesions had low biological potential and classified them in Al, focal and low grade, and A2, diffuse and high grade (3). A carefully controlled long-term follow-up by Cantrell et al. (4) indicated that tumors with a volume extent of less than 5% of the prostatic gland and a Gleason score (Table 1) of 4 or less had low clinical invasive potential and required no treatment (4,5). It is now accepted that roughly one-third of the diffuse high-grade lesions progress 665

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Table 1 Gleason grading system. Histology and staging

The combination of 1. The primary histological pattern 2. The secondary histological pattern 3. The clinical stage-stage 4 given a weighted value of 5

Score 1-5 Score 1-5 Score 1-5

The range is thus from 3-15

to clinical cancer which necessitates earlier treatment. Possible trigger mechanisms as food habits and other environmental factors that may convert latent, preclinical cancer into clinical cancer are at present the subject of epidemiological research (6). Once the diagnosis of clinical cancer is established, all studies point to the value of the prognostic factors, where the degree of differentiation of the cancer and its volume allow some prediction of progression. Poor differentiation of the tumor cells is generally accepted as a prime factor in aggressive malignant behavior. There is, however, a wide range of histological degree of differentiation which directs our actual research towards other expressions of biological behavior such as ploidy. A strong correlation exists between differentiation and volume. Basic research on the morphology and pathobiology of the prostate by McNeal (7) suggests that prostate cancer is a biological entity with a slow but constant growth rate. The malignant potential increases with time and strong correlation between capsule penetration, seminal vesicle invasion and metastatic disease and final tumor volume was demonstrated in 100 radical prostatectomy specimens. The precursor lesion of the incidental carcinoma is an even more controversial topic. Many terms and labels have been proposed for the atypical, malignant epithelial proliferations among which prostate intraepithelial neoplasia (PIN) is now the accepted term. Similarity in architecture and cytology with highest grades in the basal layer located in the peripheral zone with increased frequency and extent of PIN with prostate cancer suggest an association (8). The strong association between PIN grade 3 and the presence of prostate cancer calls for a second look whenever biopsy reports are negative in this situation. Pelvic lymph node invasion indicates as a rule generalized disease and poor prognosis. The only debate is the clinical significance of minimal nodal metastasis. Based on progression free and cancer specific survival rates, Gervasi et al. (9) demonstrated that patients with positive pelvic nodes ( N +) ran a much higher risk of generalized disease ( M l ) than those without pelvic node invasion (NO). Even patients with a single microscopically positive node developed patterns of progression of 80% _+ 15% within 10 years’ follow-up. This supports the concept that prostatic cancer is a biological entity where, from its inception, a slow and steady growth rate at all volumes can be

projected as extent of disease. This concept is considered in the nodal evaluation of the 1987 TNM classification (10). The same concept can be applied for metastatic disease and tumor burden is recognized as an important prognostic factor in metastatic disease (1 1). The natural history of untreated prostatic cancer seems to follow a slow but steady course to death determined in length of time by the extent of disease at diagnosis. Androgen withdrawal might influence the differentiation and growth of the tumor and is therefore able to delay this lethal development depending on the heterogeneity of the tumor at the time of treatment. The risk of distant metastases after transurethral resection of the prostate versus needle biopsy is probably not an effect of the surgery itself but just an expression of the association between the mass of an obstructive tumor and the risk of metastases (12). Diagnosis and Staging The diagnosis of prostate cancer is usually based on a rectal examination. Cancer is suspected in the prostate when the palpating finger detects an indurated area. Subsequent biopsy will be positive for cancer in approximately 50% of the cases in asymptomatic patients. Advanced prostate cancer in symptomatic patients is not easily missed by the index finger and almost always positive for cancer on subsequent biopsy. The rule of thumb is that symptomatic cancer is advanced and beyond cure but there are cases where the urological symptoms are caused by concomitant prostatic pathology as benign prostatic hyperplasia. On rare occasions the patient is referred for a prostate examination for elevated prostatic serum markers, osteoblastic bone lesions and suggestive histology in unidentified tumor masses elsewhere in the body. It is imperative that the clinical suspicion is confirmed by needle biopsy, aspiration cytology or, on occasion, transurethral resection in patients with obstructive uropathy. The simplicity of the examination is deceptive since graphic reproductions of the palpation in the chart of the patient varies considerably over length of time by the same or different examinors (13). This situation has been changed by the general introduction of ultrasound technology, in particular transrectal ultrasound, where a reproducible document is obtained with the indication of volume, suspicion of cancer by hypo-echoic zones and invasion of the extra prostatic space (14). Many clinical reports have now, by utilizing more advanced technology, demonstrated that gland volume, extent of tumor, response to therapy, invasion of the capsule and the seminal vesicles and direction of the biopsy needle are readily determined in a clinical setting ( I 5). We consider ultrasound the most reliable imaging technique to detect and assess prostate pathology over any radiographic technique, computed tomography and nuclear magnetic

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resonance included. Earlier expectations that the theoretical resolution of the ultrasound technology could reveal microscopic presence of tumor could, however, not be reproduced in expert hands ( 16). The most recently modified policy of the Executive Board of the American Urological Asociation is representative of expert opinion. It recognizes the clinical value of transrectal prostate ultrasonography when used as a diagnostic procedure in the evaluation and management of malignant diseases of the prostate. This is most effectively ultilized by urologists who are trained in its application and who understand its limitations for cancer detection including its specificity and sensitivity. The value of transrectal prostate ultrasonography as an independent screening procedure for the diagnosis of prostate cancer has not been established. Several screening attempts to detect unsuspected early prostate cancer in asymptomatic males have failed for a variety of reasons mostly related to the organization of the screening and its epidemiological methodology. At this moment several studies are in development or in progress such as the National Prostate Cancer Detection Project (NPCDP), coordinated by F. Lee, a prostate screening study coordinated by L. Denis for the Flemish Advisory Commission of Cancer Prevention (VACK) and a collaborative cancer screening project for colon and prostate cancer by the National Cancer Institute VSA. The final diagnosis by needle biopsy has also been under constant improvement by the introduction of ultrasound guided procedures providing core biopsies and cytological aspirations. In conclusion, like Stamey we recommend that digital rectal examination combined with ultrasound guided transrectal biopsy as an excellent base to diagnose cancer, to establish a true grade and to estimate the prostate cancer volume in the majority of cases (17). Numerous biologically active substances have been studied as potential early indicators of prostate cancer (Table 2) but none of them has passed the test of specificity/sensitivity to be effective as a screening marker (18). Recent studies suggest that prostate specific antigen has increased sensitivity/sensibility compared to prostatic acid phosphatase but both markers are variable in individual patients. Considerable overlap has been found between stages of prostatic cancer concerning elevated serum levels of prostate specific antigen and no value has been found suitable for screening purposes. However, prostate specific antigen is most useful to monitor response and predict prognosis in patients with prostate cancer under treatment (19). Once the histological diagnosis is confirmed, one has to assess the clinical extent of the disease. Beside the obvious advantage for registration and epidemiological studies, the staging and grading of the tumor is needed before adequate treatment can be given. A number of staging systems has been utilized but the

Table 2 Biological markers studied in relation to prostatic cancer

Prostatic acid phosphatases (PAP) Alkaline phosphatases and its fractions Prostate-specific antigen (PSA) Carcino-embryonic antigen (CEA) Alpha fetoprotein (AFP) Human chorionic gonadotrophin (HCG) Creatinine kinase isoenzyme (CK-BB) LDH isoenzymes Spermine and spermidine Gamma seminoprotein Oncogene products P 53 (53 K protein) V src (sarcoma) V H ras (Harvey sarcoma) V fes V fms Cancer associated antigens: Ca 549, 15-3, 19-9, 125 Cytokeratins, vimentin Tissue growth factors Antimitogenic protein (growth inhibitor) Zinc

UICC TNM staging system (20) has been adapted as a universal staging system. The system tries to follow a similar approach for all tumors and achieve simple categories of localized disease, nodal mass in number and volume and finally metastatic disease (Table 3). Simultaneously the tumor is graded histologically and/or cytologically (Table 3). This new system has met with considerable criticism from various urological groups since its adoption meant a rather abrupt change in some daily routine practice and experience. Consensus has been achieved at several levels and we expect to see proposed changes or interpretations in the near future. Most European criticism has been summarized in a publication by the EORTC TNM committee (21).

Table 3 Summary of T N M categorization and grading

Classification TI Incidental finding Tla < 3 foci Tlb 1 3 foci Present clinically or grossly, limited to gland T2 < 1.5 cm T2a > 1.5 cm/ > one lobe T2b T3 Invades prostatic apex/beyond capsule/bladder neck/seminal vesicle/not fixed Fixed or invades other adjacent structures T4 N1 Single < 2 cm Single > 2 cm < 4 cm, multiple < 5 cm N2 25 cm N3 Grade GX GI G2 G3-4

Grade cannot be assessed Well differentiated, slight anaplasia Moderately differentiated, moderate anaplasia Poorly differentiated or undifferentiated marked anaplasia

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The pathologist has to provide the grading of the cancer but is limited by the material presented. This factor is of great importance and it may be indicated in some instances to repeat the needle biopsies of the prostate. The Gleason grading system became one of the most popular systems since it allows a score from 3 to 15 which leaves room for a reasonable degree of accuracy in multiple sections of the prostate (22). The clinical staging procedures in prostate cancer are summarized in Table 4.The presence or absence of metastatic disease is the most important prognostic factor. Symptoms, high levels of markers with alkaline phosphatase included, back pain or a poor performance status are serious indications of extensive metastatic disease. The bone scan is in widespread use and has replaced all other imaging procedures to detect metabolic active areas of bone by the incorporation of wTcm diphosphatase. The reported hot spots indicative for metastatic disease are controlled by radiography. The value of the bone scan in the initial diagnosis and for detection of new lesions is undisputed but consecutive, prospective trials with exceptional quality control question the use of the bone scan to monitor disease (23,24). The lack of accuracy in some localizations as the skull has also to be recognized. In patients with obstructive urinary problems, urography might serve as a first approach since the majority of the first metastases are located in the pelvis and the lumbar spine. Unilateral hydronephrosis is an indicator of locally advanced disease and a recognized poor prognostic factor. The next step is also of prime importance and concerns assessment of the primary tumor where understaging may occur in 50% and overstaging in 15% of the cases (25). The decision to proceed to therapy with curative intent depends on the invasion of the pelvic nodes. Both com-

Table 4 Schrmr of routine staging procedures

Digital rectal examination DRE Biopsy procedures Core needle Fine needle (quadrant) Aspiration TURP* Node aspiration; Imaging IVP TRUS CT*/NMR* Urological procedures Cystoscopy* Lymphadenectomy* Markers PSA *Optional.

Table 5 Consensus proposals to assess primary tumor

I. TNM system 1987 needs modification/interpretation 2. Categories are more reliable than stage divisions 3. Grading is included in the evaluation 4. Biopsy is preferable to TUR for diagnosis 5. Rectal examination recorded on a diagram 6. Rectal examination serves in T1/T4 category 7. Ultrasound is better in T2/T3 category 8. CT/NMR do not contribute essentially

puted tomography and lymphangiography lack acceptable sensitivity and a diagnostic surgical limited lymphadenectomy is now the accepted procedure. In general, even involvement of a single lymph node classifies prostate cancer as a systemic disease even if it may take several years before the first metastases are identified. It should be remembered that a few phase I1 studies have demonstrated that the measurable metastatic and prostatic lesions behave quite differently in subpopulations of patients. The differences were of such a degree with regard to response rates and the duration of response and survival that the two characteristics (metastatic and prostatic lesions) were simply not comparable (26). The consensus proposals discussed during the latest meeting of the EORTC group in Hull (1989) are presented in Table 5.

Response criteria and prognostic factors The most widely used criteria of response to treatment are those described by the National Prostatic Cancer Project of the USA (27). They include four main categories: complete response, partial response, stable disease and progression of disease. There is a direct relationship between response and survival in the minority of patients who enjoy complete responses, disappearance of all clinical signs of tumor, or who suffer immediate progression after initiation of therapy. There exist some differences with the response criteria utilized in the trials of the EORTC urological group (28). Stable disease (SD) category is thus classified as a response in the USA whereas in Europe the corresponding category is listed as ‘no change’ (NC) category. The criteria of response vary from trial to trial but there is international consensus that phase I1 trials only should evaluate objective measurable response by a change in tumor volume or bidimensional surface area of a given mass. Measurable lesions as employed in the EORTC GU Group phase I1 studies are listed in Table 6 and the criteria of response in Table 7. It should be remembered that the effect of an individual treatment on an isolated metastatic tumor may not reflect the effect on the overall disease. It is useful to measure survival and disease-free survival in phase I1 studies but this may be misleading and it is not the prime endpoint of this type of study.

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Table 6

Table 8

Measurable lesions used as criteria of response in phase II studies

Objective criteria of progression employed in phase III studies

1. Subcutaneous nodules 2. Palpable lymph nodes 3. Nodular lung deposits-if

1. Increase in the size of measurable disease 2. New focus of disease in soft tissue or the appearance of new hot spots on bone scan confirmed by x-ray 3. Increase in size of primary tumor (primary treatment only) 4. Ureteric obstruction 5 . Death due to malignant disease

measured by chest x-ray must be at least 1 cm in diameter 4. Nodular liver deposits-if measured by CT must be at least 3 cm in diameter 5 . Lymph nodes measurable by CT scan-must be at least 3 cm in diameter 6. Osteolytic bone lesions

Table 9 Subjective parameters of progression

Table 7

I. 2. 3. 4.

Pain Loss of appetite Loss of mobility Difficulty with micturition 5 . Disruption of social activities 6. Disruption of sexual activity 7. Dependence on family and friends

Criteria of response employed by the EORTC GU Group in phase II studies in prostate cancer

A. Complete response Complete disappearance of all signs of prostate cancer and return of elevated acid phosphatase or prostatic specific antigen to normal

B. Partial response Decrease by a least 50% of the product of the two largest diameters of any measurable lesion and return of elevated acid phosphatase or prostatic specific antigen to normal. There should be no evidence of new areas of malignant disease. C. No change The no change category of response is used when there is no clear evidence of progression of remission, i.e. complete or partial response. There should be no evidence of new areas or malignant disease. D. Objective progression Increase in the product of the two maximum diameters of any measurable lesion by 25% or more. The appearance of new soft tissue metastases.

Phase 111 studies which do compare efficacy of different treatment modalities are defined by a number of endpoints usually the time lapse to subjective or objective progression and the length of survival. In prostate cancer it is indicated to evaluate both death by cancer and death by all causes. The criteria for response in the absence of measurable disease is not easy. Even defining time to progression may be divided into objective parameters as new lesions, subjective parameters as cancer related pain, laboratory parameters as elevation of prostate markers and quality of life parameters as social activities and loss of independence. Objective criteria of progression utilized in EORTC studies are listed in Table 8 and the subjective criteria in Table 9. It is prudent to state that criteria of response should be carefully evaluated and caution is advised when drawing conclusions on any comparison without evaluating time to objective progression and death. The results should be unequivocal and reproducible in most centers. Most responses are grouped together but they do appear in sequence. A patient may for instance develop a new

osteoblastic bone lesion without complaining of pain for months. An important basis for all clinical trials are the known prognostic factors which should be registered at a given point in time, usually at the time of diagnosis. Prognostic factors appearing during the treatment period are labelled intermittent prognostic factors. The prognostic factors evaluated after three phase 111 studies in the EORTC totalling more than 1000 patients are listed in Table 10. Patients entering a trial with good prognostic factors, will do well whatever therapy is given while patients with poor prognostic factors usually die with a median 18-month survival (29). We do know that prognostic factors have often more impact on survival than any form of therapy in prostate cancer. It is therefore important to evaluate the stratification in the arms of a given study to ensure equivalency before any conclusions are drawn (30). Performance status, absence or presence of pain, extent of primary tumor, extent of metastatic mass, excessive elevations of PAP and PSA as well as serum testosterone

Table 10 Prognostic factors for duration of survival (all causes of death) in decreasing order of prognostic significance. Variables retained in Cox’s ph model using a step-down procedure (EORTC 3076130762, H . a2 Voogt et al., 3, 1989) ~

Highly significant ( p < 0.001)

PS Acid

PS Alkaline

T Significant ( p d 0.05)

Marginally significant (p < 0.10)

Pain

PS T ACD

ACD

Acid & alk. Age M G

Hb Treatment

Hb Treatment

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Treatment

ordinated by F. Keuppens) comparing bilateral orchidectomy with or without systemic mitomycin C therapy. The current philosophy of treatment suggests a tailored treatment based on prognostic factors, a choice of endocrine treatment if indicated and a flexible management if treatment results do not live up to expectations.

First-line treatment in routine clinical practice usually involves some type of androgen withdrawal treatment associated with 60-80% response. However, even responders ultimately progress with disease refractory to hormonal therapy. To put it bluntly the majority of patients diagnosed with prostate cancer are in advanced incurable stages of the disease. Clinical progress is possible by making the diagnosis of prostate cancer in the early stages where loco-regional treatment may be effective. Advances in screening methodology are expected to improve our diagnostic options. Increased physician awareness, patient's acceptance, needle biopsy techniques and improved treatment options have all contributed to an upward trend in numbers of early diagnosis (31). Availability of treatment should not prevent the physician to respect the natural history of this slow growing tumor in an aged patient burdened with concomitant diseases and shortened life expectancy. The patient's quality of life is the first goal of any treatment, be it palliative. curative or expectant. There is consensus that patients with good prognostic factors for their prostatic cancer but in poor general health should have no treatment of the prostate cancer or essentially deferred treatment if the first option fails. Even if one considers hormonal treatment, we have to evaluate the treatment options and their advantages and/or toxicity before treatment is started. As explained earlier this attitude serves the patient well when dealing with tumors with low biological aggression or with tumors in the very early stages. There is no clear answer to the question of early or deferred treatment and several phase 111 prospective trials are running to solve this problem. Two of these are EORTC studies, 30892 and 30891 (coordinated by F. Schroder/U. Studer) in which patients with surgically proven node positive disease or patients with Nx MO (any T category) at initial diagnosis are randomized to immediate hormonal treatment or delayed treatment at the time of progressive disease. Progressive disease includes both objective and subjective progression. The urological group of the Medical Research Council (MRC) has initiated a study where patients with advanced asymptomatic disease MO or MI are randomized to immediate or deferred orchiectomy (coordinated by D. Kirk) (32). The opposite side of the spectre involves symptomatic patients with poor prognostic factors. There is a trend for early aggressive treatment hoping to improve overall results by combining hormonal and cytotoxic therapy at the initial diagnosis (33). The EORTC initiated a randomized study EORTC 30893 (co-

Active loco-regional treatment is curative in intent and labelled as radical by this intention only since quite sensibly both surgery and radiotherapy are seldom utilized to the limits of radicality. Surgery involves total prostatectomy with possible preservation of potency and tract reconstruction (34). Radiotherapy is given by external beam radiation or by brachytherapy usually by the implantation of iodine-I25 seed implants (35). There are proponents according to institutional expertise for each of these forms of treatment. This makes comparability between treatment results impossible due to lack of proper control series. The optimization of surgical technique (34) has been widely adopted and many urologists believe that local prostatectomy via the retropubic route after pelvic staging lympadenectomy is the preferred choice of treatment in patients with an expected 10- to 15-year survival (36). Ideal candidates for total prostatectomy are the patients with disease limited to one lobe of the prostate (T2a) in whom penetration of the capsule and involvement of the seminal vesicles are relatively rare. Prostate cancer with involvement of both lobes or even capsule invasion (T2b-T3) are subjected to surgery with variable results. The best results are reported for total prostatectomy supplemented by appropriate immediate adjunctive treatment (37). Evaluation of these results in comparison with routine clinical practice is next to impossible since we evaluate only approximately 10% of treated patients where the diagnosis of tumour extension is made by the pathologist after surgery. The most difficult problem is the treatment of T l a or T l b disease where overtreatment is real in focal disease and undertreatment is common in diffuse disease. Radiation therapy is associated with acceptable morbidity. The positive postradiation biopsy results are still controversial and as in surgery more time is needed in the overall follow-up to define the true recurrence of tumor, be it local or metastatic. There are no data showing treatment superiority for either of these two options and a National Institute of Health Development Programme recognized comparable 10-year survival rates for both treatments (38). Of most importance is the recommendation that, when considering the choice of treatment with his physician, the patient should be informed on probability of cure, mortality, morbidity, risk of impotence and incontinence, psychosocial consequences, extent and risk of pretreatment tests and the economic consequences of each form of treatment. Preliminary data suggest that both treatments could be

may all play a role in the evaluation of each new patient. Scrutiny of the most important prognostic factors/response of disease is advisable to avoid misleading statements.

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complementary if the results fail to reach the expectations of cure. Some centers proceed to radical prostatectomy when there are positive biopsies 2 years after irradiation. Adjuvant radiotherapy may be advocated when gross residual tumor margins are left after surgery. Both options deserve long-term follow-up. Caution is justified, however, since there is additional morbidity of irradiation after surgery (39). One may conclude that a careful diagnostic work-up and an in-depth interview with the patient will allow the physician to propose definitive curative treatment in selected cases, given the understanding that optimal treatment by several options is available to the patient. A safe rule of thumb is to evaluate the overall physical condition of the patient to be followed by the exclusion of M 1 disease (bone scan, elevated alkaline phosphatase, very elevated PSA levels) and the exclusion of extensive regional disease (urography, lymph node dissection in the pelvis). Hormonal therapy for advanced prostatic cancer

Ever since Huggins & Hodges (40) established in their classical paper the hormone dependence of prostatic cancer, the principal aim of treatment of this disease consists in manipulating the hormonal environment either by inhibiting the secretion of androgens or by interfering with their effects at the cellular level. Reduction of circulating androgen levels was first achieved by orchidectomy and/or estrogens. Since then other surgical procedures as adrenalectomy, hypophysectomy and medical treatment with progestagens, antiandrogens, inhibitors of androgen biosynthesis and long-acting LHRH analogues have been used either as monotherapy or in combination to reach the same goal. Recently our knowledge about the role of growth factors, oncogenes and proto-oncogenes, in the oncogenesis of prostatic cancer has yielded a new approach to the treatment of this disease. Until now, however, hormonal therapy remains only palliative and there is no consensus as to whether treatment really improves survival. Often choice of therapy depends on the personal inclination of the urologist or oncologist as many controversial points remain unanswered. Early versus delayed treatment, surgical versus medical approach, monotherapy versus combined treatment, selection between possible responders and nonresponders, the hormonal escape phenomenon, remain some of the principal controversies and no standard treatment has ever been adapted unanimously. However, for most urologists orchidectomy constitutes the treatment of choice against which the results of any new treatment should be compared (41). At present there is agreement that an overall beneficial response from first-line hormonal manipulation will be seen in about 60-80'Y0 of patients with advanced prostatic carcinoma. However, within 18 to

67 1

30 months most of them will relapse due to escape from androgen dependence. A second-line hormonal manipulation will achieve some subjective responses in 30% of those patients but within 6 months progression will recur and mean survival rarely exceeds one year. The recent concept of total androgen blockade (42) has blurred the limits between first- and second-line hormonal treatment but the definitive superiority of this form of therapy still awaits confirmation by several ongoing randomized trials comparing monotherapy with combined treatment. Orchidectomy

The testicles being the main source of testosterone (95%), their removal will induce a rapid and profound fall of circulating testosterone levels. Surgical castration is an easy and cheap procedure with low morbidity and even lower mortality. The dramatic improvement achieved by this ablative procedure is, however, after two to three years in most patients followed by relapse or progression. Orchidectomy, of course, is definitive and testosterone values will remain at castration levels as long as the patient lives. For some patients this surgical mutilation with its psychological impact is difficult to accept. Subcapsular orchidectomy leaving the testicular tunica or implantation of testicular prosthesis are useful in these patients. One should remember, however, that up to 40% of patients with advanced prostatic cancer might persist with a primary hormone unresponsive cancer and that orchidectomy in these patients will give no benefit whatsoever. Except for the psychological side effects and those associated to the lowering of testosterone, the side effects of orchidectomy are minimal. Hot flushes, occurring in 30 to 40% of patients, are rarely a real problem. Estrogens

The effects of estrogenic drugs are mainly due to their inhibitory effect on the hypothalamo-pituitary-gonadal axis, reducing LH secretion and subsequently testicular testosterone synthesis. They raise SHBG (sex hormone binding globulin) levels, lowering the amount of free active testosterone. They might also have a direct dose dependent antitumoral effect at the prostatic cellular level as has been postulated by several authors (43,44). Several steroidal (polyestradiolphosphate, ethinylestradiol) and non-steroidal synthetic compounds (diethylstilbestrol, DES diphosphate, dienestrol) have been extensively used in the treatment of advanced prostatic cancer. Diethylstilbestrol (DES) has been investigated at therapeutic doses of 5, 3 and even 1 mg/day. Although VACURG and EORTC studies confirmed its efficacy compared to orchidectomy, all those studies revealed a significant cardiovascular toxicity and associated mortality. Other side effects include feminizing symptoms such as often painful

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gynecomastia (45). For these reasons most clinicians today believe that estrogens should no longer be considered as a first-line therapy in advanced prostatic cancer. High-dose estrogens (for instance DES diphosphate Honvan) might, however, be useful in some patients in relapse after a first-line hormonal manipulation. Another compound, estramustine phosphate, an association of estradiol with nitrogen mustard, exerts simultaneously an antigonadotropin and cytotoxic effect by binding to specific microtubule-associated proteins. This drug has been used in primary untreated as well as in relapsing patients. Reported results are contradictory and most randomized studies have failed to show superior results for this regimen. Cardiovascular toxicity, although lower than with estrogens alone, remains a frequent problem. Estramustine is recommended in poorly differentiated and hormone-unresponsive cancer. An average response rate of about 35% is to be expected in these conditions (46). LHRH analogues

LHRH analogues or superagonists can downregulate LHRH receptors on pituitary gonadotrophs and induce a medical castration by lowering LH and FSH secretion and subsequent testosterone biosynthesis, when given in high and sustained doses. Several phase I1 and phase 111 studies with different LHRH analogues comparing them to estrogens and to orchidectomy have shown identical but not superior response rates in the treatment of advanced prostatic cancer, but devoid of the side effects of estrogens and orchidectomy (47). Except for the possible ‘flare-up’ phenomenon at the start of treatment, no LHRH agonist-associated toxicity has been reported. Side effects are those related to the testosterone deprivation with decrease of libido and potency. Hot flushes occur in about 40% of patients. The ‘flare-up’ phenomenon due to the initial stimulating effect on LH and testosterone has been reported with conflicting incidence rates by several groups. Clinical complications, such as pain exacerbation, worsening of ureteric compression, and paraplegia, occur in less than 4% of all cases. Biochemical aggravation, rise in PSA or PAP, has been reported in up to 20% of patients. Concomitant administration of DES or an antiandrogen started before or at the same time as the LHRH agonist treatment and, given during the 2 to 4 first weeks of treatment, prevents this possible complication (48). The use of LHRH agonist has also been suggested in order to test the hormone dependency of the tumor in a given patient by judging the response of therapy after 3 months (49). The slow release depot preparations ( I to 3 months) lower testosterone values to castration levels within the first 4 weeks, maintain these levels for more than 4-5 years and improve patients’ compliance.

Progestagens. Progesterone compounds inhibit, via a negative feedback mechanism, the pituitary LH release and consequent testosterone production. By binding the 5-alpha-reductase, responsible for the transformation of testosterone to dehydroxytestosterone (DHT), they also lower the intraprostatic DHT levels that are necessary for the function and the growth of the prostatic cells. Chlormadinone acetate (CMA) and medroxyprogesterone acetate (MPA) have been widely used. Cardiovascular toxicity, although present, is less than that related to estrogens. Randomized studies failed to show superior results with these compounds and the EORTC trial 30761 showed to the contrary that MPA was less effective than DES or cyproterone acetate (CPA) (50). Anfiandrogens. While all the foregoing surgical or medical regimens accomplish androgen withdrawal, antiandrogens block the androgen receptors in the presence of normal or even increased levels of testosterone. Antiandrogens are of two types: steroidal and nonsteroidal (pure). The first group not only interfere with the cellular androgen receptor but also display some progestogen-like antigonadotrophic activity. Cyproterone acetate (CPA) is the best known of these. The second group or pure antiandrogens displace testosterone from the androgen receptor, activating at the hypothalamic pituitary level a compensatory increase of LH, resulting in an increase of testosterone production and secretion. Although there has been concern that this rise in testosterone levels might override the blocking effects of pure antiandrogens, several reports have shown that this treatment is as efficient and safe as more classical treatment regimens. Both groups have been used either as monotherapy or in combination with orchidectomy or LHRH analogues, in order to induce what has been called maximal androgen blockade. This concept will be discussed subsequently. CPA has a slight but significant cardiovascular toxicity. Side effects of pure antiandrogens (flutamide, nilutamide) are rarely severe: gastrointestinal disturbances, liver toxicity, hot flushes and gynecomastia are the most common. Some cases of hemeralopia have been reported with nilutamide. Interestingly, but not yet explained, potency when still present at start of treatment with pure antiandrogens is sometimes maintained (51). Hypophysectomy. Except for some rare cases with intractable pain, hypophysectomy is no longer considered as an efficient tool in the management of prostatic metastatic cancer. Surgical adrenalectomy. From the 1950s to the beginning of the 1970s, adrenalectomy was performed as a secondline therapy, to remove the source of adrenal androgens. It has been shown that the prostatic cell is able to convert those into DHT, necessary for its metabolism and growth. Overall results, however, were poor with a short-lasting

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subjective response in about 20% of patients. Medical adrenalectomy has rendered this procedure obsolete. Aminoglutethimide (AG). Aminoglutethimide, initially a hypnotic drug, blocks the enzymatic system responsible for the conversion of cholesterol to delta-5-pregnenolone. Synthesis of gluco-, mineralo-, and sex steroids is, in a dose-dependent way, inhibited achieving a medical adrenalectomy. If doses of more than 500mg/day are given, hydrocortisone substitution is mandatory. AG has mainly been used as a second-line therapy in relapsing patients. Objective responses are rare but stable disease and subjective responses have been reported in about 50% of all cases. However, some of the beneficial effects might be due to the concomitant glucocorticoid substitution therapy (52). Side effects, somnolence, fatigue, rash, fever, and nausea, are quite frequent and can limit the use of this drug. Ketoconazole high dose (KffD). Ketoconazole, a known antimycotic imidazole derivative, blocks the biosynthesis of sex steroids by interfering with the cytochromo P 450 dependent testicular and adrenal enzymatic systems, when given at doses of 800-1 200 mg/day. We have shown that with 1 200 mg/day, castration testosterone values are reached within hours. Unfortunately synthesis of other steroids might also be partially or completely inhibited leading to potentially lethal adissonian crises (53). KHD achieves a complete androgen blockade but fails to produce better responses than other first-line therapeutic modalities. Its side effects, mainly gastrointestinal disturbances, weakness, and asthenia severely limit its use. Its pain relieving effect in relapsing patients, however, can be useful in selected cases. R 75251. This imidazole derivative was shown in animals and healthy volunteers to inhibit selectively androgen biosynthesis. However, our own experience with this new drug in relapsing castrated patients did not show adrenal androgen synthesis inhibition, although objective partial responses and subjective responses were seen in nearly 50% of patients. This molecule seems to act as a soft chemotherapeutic agent devoid of the Severe side effects that are generally associated with chemotherapy. The exact mechanism by which this drug exerts its beneficial effects are not yet elucidated, but might be partially related to accumulation of retinoic acid in epithelial tissues (54). Suramin. Recently suramin, a drug used for more than 50 years for the treatment of African trypanosomiasis and onchocerciasis, was shown to inhibit, by specific-binding to their cellular receptors, different tissue growth factors such as platelet derived growth factor (PDGF), epidermal growth factor (EGF), fibroblast growth factor (FGF) and transforming growth factor beta. There is also experimental evidence that suramin can counteract the stimulating effects of androgens on the growth of LNLAP cells.

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Winnal et al. (55) reported the beneficial effects of suramin in patients with relapsing metastatic prostatic cancer. We were able to confirm their results but considerable drug toxicity is a limiting factor in the use of this old new drug (56). Side effects include rash, fever, fatigue, gastrointestinal disturbances, liver and cortico adrenal toxicity, polyneuritis and coagulation disorders. Somatostufin analogues. Experimental evidence for the involvement of growth factors and their cellular receptors in the growth control of prostatic tumors has led to explore the possibility to inhibit or to antagonize the effects of the different growth polypeptides and factors. Schally & Redding (57) and others have shown in experimental Dunning PCA models a growth inhibiting effect of somatostatin super analogues. Several clinical studies at present are evaluating the effects of some of those analogues in the treatment of PCA. Other hormones or antihormones. Antiestrogens (Tamoxifen) have been reported to have some subjective effects in relapsing PCA (58). Calcitonine and third-generation diphosphonates may bring some relief in painful osteolytic metastatic disease. The total or complete androgen blockade concept. There is some evidence that the prostatic cell is able to convert the weak adrenal androgens into DHT, the bioactive hormone that is required to maintain prostatic cell metabolism and growth. As the adrenals are the main source of these weak androgens, medical or surgical castration fails to eliminate this potential source of DHT precursors. According to Labrie et a]. (59) these androgens are able to stimulate the prostatic tumor cells which are not as is commonly thought hormone insensitive, but rather hypersensitive to androgens. This might explain the remissions that have been reported after surgical or medical adrenal suppression. This concept, however, has not yet generally been accepted and many points remain very controversial. Nevertheless Labrie et al. (59) claimed very impressive results in patients treated by combination of surgical or medical castration and pure antiandrogens. Recently Crawford et al. (60), in a randomized study, reported improved survival for those patients who were treated by combination therapy compared to those treated by monotherapy LHRHA. The Daproca and the EORTC trial 30853, although not yet completed, failed to show a significant difference in favor of this new concept. Maturation of data will have to prove the superiority of this treatment modality over conventional treatment. Chemotherapy

The National Prostatic Cancer Project (NPCP) has devoted 14 years of trials on the evaluation of prostatic cancer under chemotherapeutic treatment. This extensive experience revealed that only a small number of patients

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Table 11 Single agents which have demonstrated objective response rates in men with relapsed prostatic cancer

Methotrexate Cisplatin Cyclophosphamide Doxorubicin Epirubicin

Estramustine Methyl-CCNU D. TIC Vinblastine Mitomycin C

with hormone refractory prostate cancer exhibited a favorable clinical response (61). Factors responsible for this low rate of response are the slow doubling time of the tumor, the usual bulky volume of tumor present and the frailty of the patients. An number of single agents have been identified to induce a positive clinical response (Table 11). Estramustine, cisplatinum, methotrexate, epirubicin and mitomycin C are probably the drugs currently most used. The combination of chemotherapy with hormonal therapy seems a logical sequence of some animal experiments (62). Several trials compare standard therapy versus identical therapy supplemented by mitomycin C , cyclophosphamide and doxorubicin but await maturity of data. No study results support the clearcut indication for chemotherapy but this approach seems at present to be the only rational way to obtain improved results in a phase of the disease where the expected survival is short and hormonal treatment has failed.

Management stage by stage Incidental carcinoma. The category is defined as TOpT1 (TNM 1978), Tla-Tlb (TNM 1987) and Al-A2 (USA) diseases. As explained earlier the tumors confined to less than three high-power fields with well differentiated malignancy have excellent prognosis. The question of active treatment is open in patients with a long life expectancy. As approximately one-third of the cases progress within 5 years, treatment is usually indicated. However, very often the tumor is understaged even after repeat TUR and about 25% of this population has positive nodes at the time of pelvic lymphadenectomy. Guided needle biopsies of the peripheral zone and the seminal vesicles is feasible and a more elegant treatment option. It is safe to state that primary monotherapy is especially successful in truly confined disease in particular if pathology confirms a well differentiated tumor. Here results should be evaluated over a long-term follow-up (63). An 80% 5-year survival is to be expected. Persistant local disease after treatment detected by positive margins in the specimen after surgery or high serum PSA levels after radiotherapy are routinely followed by adjunctive therapy respectively radiotherapy and hormonal treatment (64).

Poorly differentiated diffuse lesions have positive nodes in over 50% of the cases (65). Palpable localized disease. This includes categories T 1T2 (TNM 1978), T2a < 1.5 cm and T2b > 1.5 cm (TNM 1987 and B1 c 1.5 cm and B2> 1.5 cm (USA). The excellent survival of the localized nodule was very early established by the series of Jewett since most have well or moderately differentiated grades with low incidence of nodal invasion (42). These patients in the younger age group are the ideal candidates for total prostatectomy with survival approaching the theoretical life expectancy in the general population. The doubling of the tumor size involving the total gland leads to understaging and slightly lower survival results over 5 to 15 years. Poorly differentiated tumors are more common and nodal invasion is present in half of the cases. Both total prostatectomy and radiotherapy are appropriate in these categories. Locally advanced disease. This includes categories T3T4 (TNM 1978), T3T4 (TNM 1987) and C1C2 (USA), i.e. a rather heterogeneous group of tumors where fixation to adjacent structures excludes all hope for cure but where a low grade biological malignancy may be associated with a relatively long survival and favorable treatment results. At least half of the patients develop metastasis in the first 5-year follow-up and a number of therapies employed in this treatment are listed in Table 12, some with curative intent and others with palliative intent, both resulting in similar survival percentages. The major factor for the ultimate success is the invasion or not of the local lymph nodes. Local control of tumor is a secondary endpoint but important for the quality of life of the patient. Radical surgery and irradiation are two competing techniques in small sized tumors while radiotherapy supplemented by androgen withdrawal treatment is finding a new popularity. Disseminated disease. The therapy of presumed hormone sensitive prostate cancer can be achieved by reducing the available concentrations of androgenic hormones in the serum and by blocking the action of available androgens at the cellular level. Most urologists consider bilateral orchidectomy as standard primary hormonal treatment. Widely employed first-line hormonal therapies are presented in Table 13. Among newer therapy the sustained Table 12 Therapies utilized in the treatment of locaiiy advanced prostate cancer

Total prostatectomy Cysto-prostatectomy +lymph node dissection Preop. hormonal treatment Irradiation External beam Interstitial irradiation Endocrine therapy

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Table 13 Current first-line hormonal therapy in disseminated prostatic cancer

Androgen withdrawal Bilateral orchidectomy (subcapsular) Estrogens Estramustine phosphate LHRH agonists Depot preparations such as goserelin Combination treatments Estrogens and steroid antiandrogens Castration (surgical/medical) and pure antiandrogens Androgen blockade Antiandrogens Steroid class cyproterone acetate ‘Pure’ flutamide Nilutamide Casodex

Table 14 The seleciion of primary treatment

Wishes of patient

Possible treatment choice

Indifferent to sexual status

Bilateral orchidectomy Estrogens LHRH agonists Progestational antiandrogens

Fears stigma castration/ gynecomastia

Subcapsular orchidectomy LHRH agonists

Cardiovascular risk

Bilateral orchidectomy LHRH agonists

Preserve sexuality

Pure antiandrogens Trial period LHRH agonists

Fears treatment efficacy

Trial period combination treatment

release depot of luteinizing hormone agonists ( L H R H A), pure antiandrogens and estramustine enjoy renewed interest. Combination treatment results from randomized trials are still contradictory and ongoing trials will hopefully indicate advantages in time to progression and survival in certain subsets of patients. The selection of endocrine therapy for the individual patient is based on anticipated side effects, especially impotence, and the prognostic factors. The understanding of the patient can influence his choice in first-line treatment as presented in Table 14. Second-line hormonal therapy and chemotherapy are indicated in patients with progressive hormone refractory disease who unfortunately have a limited mean survival. U p to 30% of responses are reported in the literature but usually represent subjective responses. An imidazole derivative and suramin are now being tested in clinical research programs. Reliable study results are scarce in prostate cancer for several reasons. The treated tumors represent a wide variety of natural history and therapeutic response. One assumes to select ‘soft’ or minimally toxic treatment for patients with good prognostic factors while aggressive treatment is reserved for infaust prognosis. Stage, grade and prognostic factors may influence the indication and choice of treatment as presented in Table 15. Better treatment selection will depend on the outcome of actual ongoing randomized trials, the development of new drugs or existing drugs in new indications and above all basic studies on the growth potential and invasiveness of the prostate cancer cell. Defining the correct treatment for the right cancer in the patient is our clinical challenge for the next decade. Request for reprints: Prof. Louis Denis, Dept. of UrologyEndocrinology, Algemeen Ziekenhuis Middelheim, Lindendreef 1, B-2020 Antwerp, Belgium.

Table 15 Management of prostatic cancer by stage

Stage/grade

Prognostic factors

T l a G lN x MO T2aGlN x MO

Performance status Hemoglobin Pain

TlbG2-3N x MO T2bG2-3N x MO

Age Tumor size Phosphatases PSA

T3G1-3N x MO T1-4G1-3N2-3MO T1-4G1-3N X MI

Bulk metastases Chronic disease Plasma T pretreatment

Possible treatment choice Primary therapy Wait and see

Curative therapy Prostatectomy Radiotherapy

Palliative therapy Primary hormonal therapy

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REFERENCES I. Murphy GP, Natarajan N, Pontes JE, Schmitz RL, Schmidt JD, Mettlin C. The national survey of prostate cancer in the United States by the American College of Surgeons. J Urol 1982; 127: 928-34. 2. Denis L. The medical management of prostate cancer. European School of Oncology Monograph. Heidelberg: Springer Verlag, 1988: 98. 3. Jewett HJ. The present status of radical prostatectomy for stages A and B prostatic cancer. Urol Clin N Am 1975; 2: 105. 4. Cantrell BB, Deklerk DP, Eggleston JC, Boitnott JK, Walsh PC. Pathological factors that influence prognosis in stage A prostatic cancer: The influence of extent versus grade. J Urol 1981; 125: 516-20. 5. Gleason DF. Histologic grading and clinical staging of prostatic carcinoma. In: Tannenbaum M, ed. Urologic pathology: The prostate. Philadelphia: Lea & Febiger, 1977: 171. 6. Yamabe H, ten Kate FJW, Gallee MPW, et al. Stage A prostatic cancer: A comparative study in Japan and the Netherlands. World J Urol 1986; 4 136-40. 7. McNeal JE. The prostate gland: Morphology and pathobiology. In: Stamey TA, ed. 1988 Monographs in Urology: Prostate. Princeton: Custom Publishing Services, 1988: 36-54. 8. Bostwick DG, Srigley JR. Premalignant lesions of the prostate. In: Bostwick DG, ed. Pathology of the prostate. New York: Churchill Livingstone, 1990. (In press.) 9 Gervasi LA, Mata J, Easley JD, et al. Prognostic significance of lymph nodal metastases in prostate cancer. J Urol 1989; 142: 332-6. 10 UlCC (Union Intemationale contre le Cancer) TNM classification of malignant tumours. Fourth edition. Geneva: International Union against Cancer, 1987. 11 Soloway MS, Hardeman SW, Hickey D, et al. Stratification of patients with metastatic prostate cancer based on extent of disease on initial bone scan. Cancer 1988; 61: 195-202. I L . Meacham RB, Scardino PT, Hoffman GS, Easley JD, Wilbanks JH, Carlton CE Jr. The risk of distant metastases after transurethral resection of the prostate versus needle biopsy in patients with localized prostate cancer. J Urol 1989; 142: 320-5. 13. Standaert B, Van der Auwera JC, Chaban M, Cornet A, Eylenbosch W, Denis L. The use of transrectal echography for screening on prostate cancer: Results and evaluation. In: Murphy GP, Khoury S, Kuss R, Chatelain C, Denis L, eds. Prostate cancer Part B: Imaging techniques, radiotherapy, chemotherapy, and management issues. New York: AR Liss, 1987: 29-36. 14. Braeckman J, Denis L. The Practice and pitfalls of ultrasonography in the lower urinary tract. Eur Urol 1983; 9: 193-201. 15. Lee F, Torp-Pedersen ST. Siders DB, Kumasaka GH, McHugh TA. The use of transrectal ultrasound in the study of normal and abnormal anatomy of the prostate gland. In: Labrie F, Lee F, Dupont A, eds. Diagnosis and choice of therapy: Early Stage Prostate Cancer. Amsterdam: Elsevier Sci Pub1 bv, 1989: 23-36. 16. Carter HB, Hamper UM, Sheth S, Sanders RC, Epstein JI, Walsh PC. Evaluation of transrectal ultrasound in the early detection of prostate cancer. J Urol 1989; 142: 1008-10. 17. Stamey TA, Hodge KK. Ultrasound visualization of prostate anatomy and pathology. In: Stamey TA, ed. 1988 Monographs in Urology: Prostate. Princeton: Custom Pub1 Serv, 1988: 55-63. 18. Van Erps P, Mahler C, Denis L. Tumour markers in testicular and prostatic cancer. Ann Chir Gynaecol 1989; 78: 71-6. 1 1

19. Cooper EH, Armitage TG, Robinson MRG, et al. Prostatic specific antigen and the prediction of prognosis in metastatic prostatic cancer. Cancer 1990. (In press.) 20. Hemanek P, Sobin LH. TNM classification of malignant tumours. Fourth edition. Geneva: International Union against Cancer, 1987. 21. Schroder FH, Cooper EH, Debruyne FMJ, et al. TNM classification of genitourinary tumours 1987. Position of EORTC Genitourinary Group. Br J Urol 1988; 62: 502-10. 22. Gleason DF. Histology, grade, clinical stage and patient age in prostate cancer. In: Conference on the Management of Clinically Localized Prostate Cancer. NCI Monographs 1988; 7: 3-6. 23. Smith PH, Bono A, Calais da Silva F, et a]. Some limitations of the radioisotope bone scan in patients with metastatic prostatic cancer: A sub-analysis of EORTC trial 30853. Cancer 1990; 66 (Suppl. 5 ) : 3-10. 24. Dann J, Castronovo FP, McKusick K, Griffin PP, Strauss HW, Prout GR Jr. Total bone uptake in management of metastatic carcinoma of the prostate. J Urol 1987; 137: 444-8. 25. Schroder FH. Prostatic carcinoma: Comments on radical surgical treatment. %and J Urol Nephrol 1980; 55 (Suppl): 181-5. 26. Jones WG, Bono A, Verbayers A, et al. Can the primary tumour be used as the sole parameter for response in phase I1 chemotherapy studies in metastatic prostate cancer? An EORTC Genito-Urinary Group Report. World J Urol 1986; 4: 176-81. 27. Murphy GP, Slack NH. Response criteria for the prostate of the USA National Prostatic Cancer Project. Prostate 1980; 1: 375-82. 28. Newling DWW. Criteria of response to treatment in advanced prostatic cancer. In: Furr BJA, Denis L, eds. Clinical oncology: prostatic cancer. London: Bailliere, 1988: 505- 19. 29. De Voogt HJ, Suciu S, Sylvester R, et al. Multivariate analysis of prognostic factors in patients with advanced prostatic cancer: Results from 2 European organizations for research on treatment of cancer trials. J Urol 1989; 141: 883-8. 30. Denis L. The medical management of prostatic cancer. Monograph 1990 European School of Oncology. Heidelberg: Springer-Verlag, 1990. (In press.) 31. Schmidt JD, Mettlin CJ, Natarajan N, et al. Trends in patterns of care for prostatic cancer 1974-1983: Results of surveys by the American College of Surgeons. J Urol 1986; 136: 416-21. 32. Kirk D. Trial and tribulations in prostate cancer. Br J Urol 1987; 59: 375-9. 33. Murphy GP. Evaluation and results of chemotherapy of prostate cancer. In: Lapis F, Ekkhardt S , eds. Medical oncology. Basel: Karger/Budapest, AkadCmia Kiado, 1987; 183-8. 34. Walsh PC. The role of radical prostatectomy in the management of prostatic cancer. Cancer 1987; 60:526-37. 35. Plowman PN. The case for radiotherapy. In: Furr BJA, Denis L, eds. Clinical oncology: Prostatic cancer. London: Bailliere, 1988: 659-73. 36. Gibbons RP, Correa RJ, Brannen GE, Mason JT. Total prostatectomy for localized prostatic cancer. J Urol 1984; 131: 13-6. 37. Zincke H, Utz DC, Taylor WF. Bilateral pelvic lymphadenectomy and radical prostatectomy for clinical stage C prostatic cancer: Role of adjuvant treatment for residual cancer and in disease progression. J Urol 1986; 135: 1199-205. 38. Office of Medical Applications of Research, National Institutes of Health, Bethesda The management of clinically, localised prostate cancer. JAMA 1987; 258: 2727-30.

PROSTATIC CANCER

39. Walsh PC. Adjuvant radiotherapy after radical prostatectomy: Is it indicated? J Urol 1987; 138: 1427-8. 40. Huggins C, Hodges CV. Studies in prostatic cancer. I. The effects of castration, of estrogens and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res 1941; 1: 293-7. 41. Seftel AD, Resnick MI. Rationale for surgical castration. In: Furr BJA, Denis L, eds. Clinical oncology: Prostatic cancer. London: Bailliere, 1988: 527-34. 42. Labrie F, DuPont A, Belanger A. Complete androgen blockade for the treatment of prostate cancer. In: De Vita VT Jr, Hellman S, Rosenberg SA, eds. Important Advances in oncology. Philadelphia: JB Lippincott, 1985: 193-217. 43. Altwein J. Estrogens in the treatment of prostatic cancer. In: PavoneMaculuso M, Smith PH, eds. Cancer of the prostate and kidney. New York: Plenum Press, 1983: 317-28. 44. Schulze H, Isaacs JT, Coffey DS. A critical review of the concept of total androgen ablation in the treatment of prostate cancer. In: Murphy GP, Khoury S, Kuss R, Chatelain C, Denis L, eds. Prostate cancer. Part A: Research, endocrine treatment and histopathology. New York: AR Liss, 1987: 1-19. 45. Byar DP. Proceedings: the Veterans Administration Cooperative Urological Research Group’s studies of cancer of the prostate. Cancer 1973; 32: 1126-30. 44. Smith PH, Suciu S, Robinson MRG, et al. A comparison of the effect of diethylstilbestrol and low dose estramustine phosphate in the treatment of advanced prostatic cancer: A phase I1 trial of the EORTC Urological Group. J Urol 1986; 136: 619-23. 47. Namer M. Rationale for medical castration. In: Furr BJA, Denis L, eds. Clinical oncology: Prostatic cancer. London: Bailliere, 1988: 535-46. 48. Mahler C, Denis L. Simultaneous administration of a luteinizing hormone releasing hormone agonist and diethylstilbestrol in the initial treatment of prostatic cancer. Am J Clin Oncol 1988; 1 1 (SUPPI. 2): S127-8. 49. Newling DWW. The value of reversible androgen suppression as a diagnostic test. In: Murphy GP, Khoury S, Kuss R, Chatelain C, Denis L, eds. Prostate cancer. Part A: Research, endocrine treatment, and histopathology. New York AR Liss, 1987: 261-5. 50. Pavone-Macaluso, M, De Voogt HJ, Viggiano G, et al. Comparison of diethylstilbestrol, cyproterone acetate and medroxyprogesterone acetate in the treatment of advanced prostatic cancer: Final analysis of a randomized phase 111trial of the European Organization for Research and Treatment of Cancer Urological Group. J Urol 1986; 136: 624-31. 51. Lund F, Rasmussen F, Flutamide versus stilboestrol in the treatment of advanced prostatic cancer: A randomized prospective study. Poster presented at the 4th European Conference on Clinical Oncology, Madrid, 1987. 52. Murray R, Pitt P, Aminoglutethimide in the treatment of advanced prostatic cancer. In: Murphy GP, Khoury S, Russ

677

R, Chatelain C, Denis L, eds. Prostate cancer. Part A Research, endocrine treatment, and histopathology. New York: AR Liss, 1987: 275-82. 53. Mahler C, Denis L, De Coster R. The endocrine effect of ketoconazole high doses (KHD). In: Murphy GP, Khoury S, Kuss R, Chatelain C, Denis L, eds. Prostate cancer. Part A: Research, endocrine treatment, and histopathology. New York: AR Liss, 1987: 291-7. 54. Mahler C, Denis L, De Coster R. The effects of a new imidazole derivative in advanced prostatic cancer. A preliminary report. In: Murphy GP, Khoury S, eds. Therapeutic progress in urological cancer. New: AR Liss, 1989: 205-9. 55. Winnan Ewing M, Larocca RV, Stein CA, Myers CE, Linehan WM. Effect of Suramin on proliferation of human prostate carcinoma. Proc AACR 1989; 30: 310. 56. Van Oosterom AT, De Smedt EA, Denis LJ, et al. Suramin for prostate cancer: a phase 1/11 study in advanced extensively pretreated disease. Eur J Cancer 1990; 26: 422. 57. Schally AV, Redding TW. Somatostatin analogs as adjuncts to agonsits of LHRH in the treatment of experimental prostate cancer. Proc Natl Acad Sci USA 1987; 8 4 7275-9. 58. De Voogt HJ. Second-line endocrine managment: Anti-androgens and anti-estrogens. In: Schroder FH, Richards B, eds. Therapeutic principles in metastatic prostate cancer. New York: AR Liss, 1985: 351-7. 59. Labrie F, Dupont A, Btlanger A. The importance of combination therapy with flutamide and castration (LHRH agonist or orchiectomy) in previously untreated as well as previously treated patients with advanced prostate cancer. In: Klijn JGM, Paridaens R, Foekens JA, eds. Hormonal manipulation of cancer: Peptides, growth factors and (anti)-steroidal agents. New York: Raven Press, 1986. 60. Crawford DE, Eisenberger MA, McLeod D, et al. A Controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med 1989; 321: 419-24. 61. Gibbons RP (1987) Prostate cancer chemotherapy. Cancer 1987; 60: 586-8. 62. Isaacs JT, Heston WDW, Weissman RM, Coffey DS. Animal models of hormone sensitive and insensitive prostatic adenocarcinoma: Dunning R-3327-H, R-3327-HI, and R-3327-AT. Cancer Res 1979; 38: 4353-4359. 63. Lange PH. Controversies in the management of apparently localized carcinoma of prostate. Urology 1989; 34( Suppl.): 13-7. 64. Schellhammer PF, Whitmore RB, Kuban DA, El-Mahdi AM, Ladaga LA. Morbidity and mortality of local failure after definitive therapy for prostate cancer. J Urol 1989; 141: 567-71. 65. Donohue RE, Mani JH, Whitesel JA, et al. Pelvic lymph node dissection. Guide to patient management in clinically locally confined adenocarcinoma of prostate. Urology 1982; 20: 55965.

Prostatic cancer. An overview.

Reliable study results are scarce in prostate cancer for several reasons. The treated tumors represent a wide variety of natural history and therapeut...
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