39.8 Cancer of the prostate Oxford Textbook of Surgery 39.8 Cancer of the prostate John Naitoh, Jean B.

deKernion, and Daniel Shoskes

Introduction Prostate cancer is the most common cancer found in American men, and is the second leading cause of cancer death. In 1997, approximately 209 900 new cases were diagnosed in the United States alone, with over 41 800 deaths attributed to this malignancy. However, despite these large numbers, there continues to be controversy about the use of screening tests that can detect cancer in asymptomatic individuals, and about the optimal treatment if a localized (organ-confined) prostate cancer is diagnosed. Here we will first review the non-controversial' aspects of pathology, epidemiology, and the clinical presentation of prostate cancer. Then we will discuss the controversies that surround its diagnosis and treatment, including the risks and benefits of watchful waiting', radiotherapy, and surgery. Epidemiology and genetics Prostate cancer is a common finding at autopsy, but it is a cause of death in only a relatively small proportion of men. Although 60 to 80 per cent of 80-year-old men have histological evidence of prostate cancer, only 3 per cent of men will actually die from it. The present problem is the clinical differentiation between an incidental, nonlethal and a clinically significant, potentially lethal tumor. Despite the fact that the majority of men will develop only incidental tumors, prostate cancer is yet a major cause of disease and death throughout the world. In the United States it ranks second to lung cancer as a cause of cancer deaths in men, with the lifetime risk for developing a clinically apparent prostate cancer ranging between 5 and 8 per cent. While the median age for clinical diagnosis is currently 72 years, this average will probably decrease over time because increasing numbers of younger men are having their cancer detected in prostate-specific antigen (PSA)-based screening programmes. Family history is one of the most important risk factors for the development of prostate cancer. First-degree relatives of those with this cancer have an eightfold increased risk, especially if the cancer becomes clinically manifest at a younger age (below 60 years). Recently, a highly penetrant but rare familial prostate cancer gene

was localized to the chromosome region 1q2425. While this gene is believed to be involved in only about one-third of all familial prostate cancers, over 80 per cent of men who have this susceptibility gene will develop a clinically significant prostate tumor as compared to the 5 per cent incidence found in non-carriers of this gene. Epidemiological studies show marked geographical and racial differences in the incidence of prostate cancer. North Americans (especially African Americans) and Western Europeans have the highest rates of clinically significant prostate cancer, while Asians living in the East have the lowest. Interestingly, while the mortality rates show significant geographic variance, the autopsy prevalence (i.e., the incidence of clinically insignificant prostate cancer) is fairly constant worldwide. As immigration from a low-incidence to a high-incidence country results in the eventual elevation of the individual's cancer risk to that of the adopted country, it has been hypothesized that environmental and dietary factors are more important than ethnic factors for the development of a clinically significant prostate cancer. Low dietary vitamin D, low selenium, and high dietary fat have all been correlated with the development of prostate cancer, but dietary fat intake has proved of particular interest. Because dietary fats can be metabolized into steroid hormones, it has been proposed that high-fat diets result in altered metabolism of testosterone, which may then be able to promote the growth and development of prostate cancer. As a corollary, it has also been shown that low-fat diets or diets enriched in w-3 fatty acids or soy proteins can decrease testosterone production and create an environment that is adverse for the development of prostate cancer. Grading systems There are several existing systems for grading adenocarcinomas by their risk for progression, but the most popular is the Gleason, which a3signs t8e tumor`cells to a category ranging from 1 to 5 based on their degree of differentiation, gland formation, and their relation to the stroma. Given that multiple histological patterns are usually found within a given tumor, the Gleason score that is the sum of its two most common patterns is commonly used. Gleason sum scores can therefore range from 2 (most well differentiated) to 10 (most poorly differentiated). In general the Gleason score can be correlated with the stage of the tumor and the overall prognosis. However, while the Gleason system is simple and reproducible, it has some limitations. First of all, determining the Gleason score of a prostate tumor from a few needle biopsies has proved difficult and unreliable. Up to 40 per cent of core biopsies will underestimate the actual grade of the cancer found once the entire prostate has been removed and examined. Secondly, while the Gleason score provides very useful prognostic information if it is

less than 3 or greater than 7, the information obtained from intermediate Gleason scores is less useful. Thus, owing to the limited prognostic information obtained from the Gleason system on the biological potential of a given tumor, many other systems and tumor markers have been devised with the hope of gaining more accurate information. Besides the creation of other grading systems that consider cellular morphology as well as glandular structure, it has also been proposed that flow cytometry (tumor DNA ploidy), p53, p27, and other molecular markers may all be able to provide a more accurate prognosis than the Gleason score and clinical staging. Modes of spread In its early stages, prostate cancer is confined to the gland by the thin surrounding capsule. In its more aggressive form, it can escape the confines of the gland, either at the apex (where there is no gland capsule) or by lateral penetration through the capsule. The most common point of direct spread is where the erectile nerves perforate the prostate capsule along the posterolateral aspect of the gland, although the cancer can also invade the capsule anteriorly, or it can spread into the seminal vesicles or the bladder neck. The primary lymphatic drainage of the prostate is via the internal iliac, perivesical, external iliac, obturator, and presacral nodes. The secondary lymphatic drainage includes the inguinal, common iliac and para-aortic nodes. Despite this well-described pattern of lymphatic drainage, up to 15 per cent of patients who have lymphnode metastases will have skip lesions' that bypassed the primary drainage sites and went directly to the common iliac or para-aortic chains. Hematogenous dissemination can also occur, based on the finding that the majority of patients who have advanced prostate cancer will also have detectable prostate cells circulating in the peripheral blood and bone marrow. A rich venous plexus surrounds the prostate and connects to the venous drainage of the spine: this collection of veins (Batson's plexus) is potentially one of the reasons why spinal metastases are common in advanced prostate cancer. In addition, prostate cancer cells themselves have a direct tropism to bone, with bone metastases occurring in 85 per cent of patients who die of prostate cancer. However, unlike other neoplasms, prostate cancer induces the formation of blastic not lytic bone lesions. Thus, whenever an older man presents with bone pain and the plain radiograph shows an osteoblastic lesion, the primary differential diagnosis is metastatic prostate cancer. Staging systems By convention, the International Union Against Cancer TNM system is

currently the standard staging system used in the medical literature. Updated in 1997, the TNM system is largely based on the findings of the digital rectal examination (Table 1).

Table 1 The 1997 American Joint Committee on Cancer clinical staging ystem for prostate cancer (TNM)

Screening For a screening programme to be effective, the cancer must be detectable with minimal discomfort, low risk, and acceptable financial cost. Early diagnosis must also be able to improve the quantity and quality of the patient's life; there must be an effective treatment available for the cancer; the treatment must be acceptable to the patient; and active treatment of the asymptomatic patient must be able to provide a better outcome than observation alone. There is at present no evidence that screening for prostate cancer based on the PSA blood test fulfils all of the requirements of an effective screening programme. If the detection of prostate cancer is based on the presence of voiding symptoms or on the findings by digital rectal examination, then only a minority of patients will be found to have curable, localized disease at the time of diagnosis. On the other hand, if screening with PSA is able to detect a significant number of tumors that will not actually shorten the patient's life, then the morbidity and mortality of that screening and subsequent treatment could be worse than the disease. Unfortunately, it is as yet not known whether screening programmes are resulting in the overor undertreatment of prostate cancer. Despite these uncertainties, there is some evidence that screening for prostate cancer is beneficial. First, there is evidence that PSAbased screening programmes are able to detect only clinically significant tumors (i.e., larger and more aggressive tumors that will cause significant symptoms or decrease the patient's lifespan if left untreated). Secondly, given the lack of effective treatments for advanced prostate cancer, early detection and treatment is currently the only approach that can decrease its death rate. And finally, there is some evidence that the aggressive diagnosis and treatment of

prostate cancer is having an effect: decreases in its incidence and mortality rate were seen for the first time in 1997. While it is too early to attribute these changes to the implementation of the screening programmes that began in the mid-1980s, PSA-based screening programmes have demonstrably resulted in a decrease in the number of patients who present with metastatic tumors or a markedly elevated PSA. Given the lack of concrete evidence to support or refute the benefits of a screening programme for prostate cancer, the decision to offer such screening must be made on an individual basis, depending on the patient's age, health status, family history, personal risk for prostate cancer, and his personal beliefs. However, it must also be remembered that there are some who should undergo intensive evaluation because they have an increased risk of dying from prostate cancer. These individuals at risk include all African American men, and, as explained earlier, all men who have a first-degree relative with prostate cancer. In these men there may be a genetic predisposition to aggressive prostate cancer, and the American Urologic Association recommends their evaluation with annual PSA tests and rectal examinations beginning at the age of 40 years. For all other men, once they understand the risks and benefits of screening, as outlined above, testing for prostate cancer should begin at the age of 50 if they desire it. Following an initial screening, annual examinations can then be considered, with any changes on rectal examination or a PSA rise of greater than 0.7 ng/ml per year serving as an indication for biopsy. Once the patient is over the age of 70, or once he develops significant underlying illnesses or another incurable malignancy that will decrease his life expectancy to less than 10 years, then screening for prostate cancer can be halted. Diagnosis For many years, prostate cancer could only be detected from an abnormal finding on digital rectal examination, an elevated prostatic acid phosphatase, and the results of transperineal biopsy. Over the last 10 years, new methods have proliferated (transrectal ultrasoundguided prostate biopsies, serum PSA) that have made the diagnosis of prostate cancer easier (Fig. 1). This has resulted in a large increase in the numbers of patients diagnosed.

Fig. 1. Transrectal ultrasound image of prostate. Note hypoechoic

nodule (arrow) found to be adenocarcinoma on biopsy.

Indications for evaluation For any male with voiding difficulties, or where there are signs and symptoms of metastatic cancer, a search for prostate cancer is reasonable. Such patients may have symptoms due to prostate cancer. In these circumstances, either curative treatments (such as radical prostatectomy or radiation therapy) or palliative treatments (such as hormone therapy) can be used to decrease the symptoms and improve quality of life. Patients who have an abnormal finding on digital rectal examination should also be tested for prostate cancer. In general, any area of asymmetry, nodularity, or induration in the prostate should be evaluated (by either a finger- or ultrasound-guided needle biopsy), since up to 50 per cent of these changes will be caused by cancer. However, while digital rectal examination is cheap, rapid, and well tolerated, the problem with using it alone as a screening tool is its lack of specificity and its inability to detect cancers before they have spread. Over 50 per cent of patients whose cancer was detected by digital rectal examination had already developed locally advanced or metastatic disease at the time of diagnosis. PSA blood test The discovery of PSA has revolutionized the diagnosis and treatment of prostate cancer. The traditional method of direct palpation of the prostate was only able to detect cancers after they had become large and therefore had a greater chance of being advanced. In contrast, PSA allows the detection of tumors before they become palpable, and therefore can detect cancer at an earlier stage. PSA is a 34-kDa protein produced by the glandular tissue of the prostate. While it is largely prostate-specific, small amounts can also be found in the periurethral and salivary glands, although these traces are usually serologically undetectable and are therefore clinically insignificant. The detection of PSA in serum is related to the extent of its leakage from the prostate. Overall, the leakage is relatively lower from benign than cancerous tissue: serum PSA is increased by only 0.3 ng/ml per gram of hyperplastic tissue, but by approximately 3.5 ng/ml per gram of tumor. Thus, while there is a potential overlap in serum PSA between men who have cancer and those who simply have very large prostates, cancer overall causes a greater rise in PSA per gram of tissue than benign prostatic hypertrophy, with the generally accepted normal range for PSA being between 0.0 to 4.0 ng/ml.

When this point is used as a cut-off value, the sensitivity of PSA in detecting cancer is between 73 and 87 per cent. However, the performance characteristics of PSA are highly dependent on the population tested and the relative risk of its members having a malignancy. For those who have a prostate nodule, approximately 50 per cent will be found to have prostate cancer independent of the value for serum PSA, and all of these men should be biopsied however low their serum PSA (interestingly, in this group of men, 20 per cent who are diagnosed with a prostate cancer after an abnormal finding on digital rectal examination will have a normal' PSA of less than 4.0 ng/ml). In contrast, for men who have a normal prostate on digital rectal examination, the incidence of cancer is between 4 to 7 per cent for those who have a PSA of less than 4.0 ng/ml, and between 31 to 42 per cent for those who have a PSA of greater than 10 ng/ml. Despite the enthusiasm for PSA as a screening tool, there are definite limitations to its use. One concern about the widespread use of PSAbased screening is the detection of indolent, clinically insignificant tumors. As was discussed above, histological evidence of prostate cancer is almost an inevitable consequence of aging, with cancers that progress to cause illness and death affecting only 8 per cent of all men. Theoretically, since PSA-based screening programmes can detect small tumors before they are palpable (clinical stage T1c), it is possible that some of these will be so small and slow growing that they will never represent a threat to the patient's health or life. However, recent data, as mentioned above, suggest that PSA-based screening programmes are picking up only clinically significant, potentially lethal tumors. It must also be remembered that PSA is just prostate specific, and not cancer specific, with the serum PSA only reflecting the amount leaking into the bloodstream from the prostate. Thus, any other medical condition that increases the volume of benign prostate tissue (such as benign prostatic hypertrophy), or any condition that can increase the leakage of PSA into the bloodstream (such as perineal trauma, urinary-tract infection, prostatitis, urethral catheterization, prostate biopsy, or recent ejaculation) can cause the PSA to rise into the abnormal range. Due to these confounding factors, the specificity of PSA is limited, with only 25 per cent of men who have a PSA of more than 4.0 ng/ml actually having prostate cancer. Beacuse of the low specificity of the PSA test, whereby four patients will have to undergo evaluation with prostate ultrasonography and biopsy for every cancer that is detected, many perturbations of PSA have been devised to improve its performance. PSA velocity, free PSA, and age/racial adjustments have all been proposed as ways of improving the specificity of PSA as a screening test. PSA velocity uses the rate of change in PSA over time to predict the

presence or absence of prostate cancer. In the normal prostate, hyperplasia and hypertrophy occur with aging, resulting in a slow but steady increase in serum PSA. Given that cancer cells proliferate more quickly than benign prostate cells, the serum PSA will rise more rapidly in the man who has cancer than in one who has a benign condition such as hypertrophy. While a change in PSA of greater than 0.75 ng/ml per year can indicate the presence of cancer (sensitivity 72 per cent, specificity 90 per cent), the utility of PSA velocity has been limited by the 15 per cent error of the PSA test itself, and by the other benign conditions (such as infection, inflammation) that can spuriously increase the PSA. The recent discovery of multiple forms of PSA in the bloodstream has resulted in the development of new screening tests for prostate cancer. PSA is normally found conjugated to a1-antichymotrypsin in the bloodstream, with cancer tissue making more a1-antichymotrypsin than normal tissue. Thus it was expected that the free (unconjugated) PSA would be lower in those with prostate cancer than in healthy individuals. Early studies found that free PSA ratios were lower in men with prostate cancer than in those with benign prostatic hypertrophy, with later reports showing that the average free:total PSA ratio was 0.18 in those with prostate cancer and 0.28 in benign prostatic hypertrophy. Subsequent studies showed that free:total PSA ratios appear to have the greatest utility when the PSA is between 3 to 10 ng/ml, where the diagnosis of cancer is less certain. In this group, the specificity of the free:total PSA test was better than that of the PSA alone, while the sensitivity of the two tests was nearly identical. By using the free:total PSA test, up to 40 per cent of the negative biopsies could have been eliminated if a cut-off value of 0.20 had been applied prospectively to the study population. Later studies disputed the idea that there is a single free:total PSA value that can accurately discriminate between cancer and benign prostatic hypertrophy. Cut-off values adjusted to different prostate sizes or different PSA values have been proposed as ways to improve further the utility of the free:total PSA test. By using these adjustments, the 90 per cent sensitivity for cancer detection was preserved, while eliminating 33 per cent of the unnecessary biopsies. Thus, free:total PSA has the potential to improve the ability of PSA to discriminate between cancer and benign prostatic hypertrophy. This appears to be especially true in men whose PSA is between 4 and 10, since the risk of cancer is more definitive at the extreme ranges of PSA. Interestingly, free:total PSA might be particularly useful in younger men whose absolute PSA is low but whose PSA is abnormal based on age-adjusted ranges. Up to 15 per cent of these men will be diagnosed with cancer during serial evaluation. The application of a free:total PSA ratio cut-off of 0.23 identified 93 per cent of the men in

this category who had prostate cancer and reduced the number of negative biopsies by 30 per cent. The free:total PSA might also be useful in the serial evaluation of a man who has an elevated PSA but a history of multiple negative prostate biopsies; in our practice, the free:total ratio is used to decide if he can safely be observed, or if more extensive biopsies are needed. Out of all of the different adjustments made to improve the performance of PSA as a screening test, the best appears to involve the use of age-adjusted ranges. With the recognition that (i) the prostate will increase in size with age, and (ii) PSA increases with age, it was logical to conclude that the normal range of PSA will also increase with age. From population-based studies of men who have no evidence of cancer, the mean and 95 per cent confidence intervals for PSA have been established, and these values have been indexed to patient age (see Table 2).

Table 2 PSA reference ranges normalized for patient age and ethnicity

By using these reference ranges, it was argued that these normal values would increase the detection of cancer in younger men who will have a greater likelihood of benefiting from screening and treatment, while decreasing the numbers of older men who undergo prostate biopsy where the benefits of cancer detection are less certain. It was predicted that these reference ranges would result in a 15 per cent increase of cancer detected in men under 60 years of age, while it would decrease the number of biopsies performed in men over 70 years old by 44 per cent. Subsequent to the development of age-adjusted ranges, the next logical step was an adjustment for ethnicity given the different rates of prostate cancer seen in Caucasians, Asians and African Americans. Asians appear to have low rates of prostate cancer, and have correspondingly low PSA. In contrast, African Americans have high incidences of high-grade, aggressive prostate cancer, and therefore also need a lower limit for PSA in order to maximize the detection of their tumors while they are still curable (see Table 2).

In summary, the main limitation of PSA as a tumor marker is the fact that it is prostate specific not prostate cancer specific. The optimal definition of normal' for PSA is still undefined, with age adjustments, ethnic adjustments, or determination of the amount of PSA bound to plasma proteins all ways that potentially could improve its specificity. Unfortunately, none of these methods is ideal, with improved specificity often at the cost of lowered sensitivity. Thus the search for new tumor markers has continued. Prostate-specific membrane antigen, human kallekrein, prostate stem-cell antigen, and DD3 are some of the molecular candidates that may replace PSA as the nextgeneration marker for the early detection of prostate cancer, with the hope that they will not just be prostate specific but also cancer specific. Management of localized disease Pretreatment evaluation The standard pretreatment evaluation of the patient who has localized prostate cancer involves tumor staging, an evaluation of comorbidity, and as a baseline assessment of urinary and sexual function. Unfortunately, at this time there is a paucity of published information on how these factors can be accurately and easily measured in clinical practice. For standard presurgical staging, most practitioners use a combination of the digital rectal examination, PSA, bone scan (in selected patients), and CT scan (in selected patients). Digital rectal examination has been the mainstay of clinical staging because it is cheap, rapid, and relatively non-invasive. However, it is affected by significant interobserver variability, by limited diagnostic accuracy, and by poor sensitivity. While the presence of T3 or T4 disease on digital rectal examination is very specific, there is also a tendency for it to understage the cancer that has spread microscopically (see Table 3). With these difficulties, digital rectal examination is relatively unreliable for determining the presence or absence of organ-confined disease.

Table 3 The risk that clinical staging underestimates the actual volume of prostate tumors

With improved understanding of the biology of PSA, this serum marker has also been used to stage patients before surgery. In studies on surgically treated patients, those who had a preoperative PSA of less than 4 ng/ml were almost uniformly cured by radical prostatectomy. In addition, patients whose PSA is less than 10 ng/ml demonstrably have an extremely low risk of detectable skeletal metastasis, and therefore do not need a staging bone scan before treatment. Finally, in those who have small, low-grade prostate tumors with a low PSA, the staging pelvic lymphadenectomy can also be deferred, owing to their low incidence of metastasis. In contrast, once the PSA is greater than 10 to 20 ng/ml, then the chance that organ-confined cancer will be found at operation is markedly decreased, and the risk that cancer will recur after treatment is markedly increased. Similar data are recorded in the radiotherapy literature, where a pretreatment PSA of greater than 20 to 30 ng/ml is regarded as a probable reflection of occult metastatic disease. However, the utility of PSA in staging is limited in the majority of patients who have clinically localized prostate cancer. PSA has not performed well when used alone as a staging tool in some case series, owing to the fact that most patients who undergo surgery have a PSA that is only mildly elevated (between 4 and 10 ng/ml), and given that there are cases where the PSA is elevated by conditions other than prostate cancer. Thus, the absolute PSA may not reflect the patient's actual tumor burden or stage. The radionuclide bone scan is also a standard part of staging for the patient with localized prostate cancer. Given its propensity to spread to the axial skeleton, bone scans can identify patients who have metastatic disease and who therefore will not benefit from surgical treatment. Unfortunately, bone scans lack both sensitivity and specificity, with other medical diseases such as healing fractures, degenerative joint disease or Paget's disease yielding false-positive results: MRI or plain radiographs are often needed to confirm the diagnosis. Furthermore, given the low incidence of skeletal metastasis in patients who have low-grade, low-stage tumors, the bone scan can usually be deferred if the PSA is less than 10 ng/ml. In contrast, the risk of skeletal metastasis is markedly increased once the pretreatment PSA is greater than 20 to 30 ng/ml: in these patients, a bone scan is required to rule out the presence of skeletal metastasis. The use of other imaging studies for staging prostate cancer is more controversial. Historically, CT scanning had only limited utility for cancer staging because of its low level of resolution. However, recent technical advances have improved its ability to detect smaller structures, and it has been suggested that modern (spiral or thin-cut)

CT scanning might have the highest sensitivity of all current imaging methods for detecting the presence of nodal metastasis. The advantages of CT scanning are that it can identify small but pathologically enlarged lymph nodes (more than 1 cm across), and provide a route for biopsy of these suspicious lesions without the need for surgery. However, the main limitations of CT scanning are its lack of specificity (since inflammatory, non-cancerous nodes are also be detected), its inability to provide information about the local extent of the primary tumor, and its inability to detect micrometastatic disease. Others have proposed that MRI can provide additional information on staging for clinically localized prostate cancer, especially where clinical staging and PSA provide ambiguous information. Limited studies have shown that MRI (especially endorectal-coil MRI) can provide useful information on capsular penetration and invasion of the seminal vesicles where the PSA and digital rectal examination are indeterminate. Some studies have also shown that MRI findings can independently predict the occurrence of PSA relapse after radical prostatectomy. MRI cannot, however, be considered a standard method for staging as these results have not been replicated at many other centres, and the equipment required for endorectal-coil MRI is available in only a few places. In summary, the standard staging for the patient with prostate cancer involves the pretreatment PSA and digital rectal examination. In those who have small prostate nodules and a PSA of less than 10 ng/ml, no further evaluation is needed. In contrast, those who have a PSA greater than 10 ng/ml should have a bone scan, while CT scanning or MRI can also be used in selected circumstances, although the data supporting their use are more limited. Treatment options for localized prostate cancer While it is clear that many men will benefit from aggressive treatment with surgery or radiotherapy, it is also apparent that some who have a clinically localized prostate tumor will be overtreated, owing to the indolent nature of their tumors, while others will have a recurrence after therapy despite a thorough staging evaluation. However, as there is no biomarker that can reliably separate those who have indolent cancers from those who have biologically aggressive lesions, and as there is no reliable method for detecting the presence of micrometastatic disease, all men who have a localized prostate cancer and a reasonably long life expectancy should consider undergoing treatment rather than watchful waiting'. Treatment for the man who has a clinically localized prostate cancer should be tailored to his individual characteristics, and to the grade and stage of his tumor. To date no randomized trial has compared equivalent populations of patients and definitively shown a survival benefit for either radical prostatectomy or radiation therapy.

Interpretation of treatment outcomes is further complicated by the understanding that many will survive equally long without any therapeutic intervention other than endocrine therapy and symptomatic treatment of metastases. The variable behavior of prostate cancer and the confounding presence of other illnesses in the age group affected make objective interpretation of the available data impossible. Until a test is developed that can accurately define the potential lethality of a specific tumor in a specific patient who has other specific illnesses, other criteria must be used by the individual in his choice of treatment, more often based on the risks of sideeffects than the chance of cure. Side-effects of therapy must be considered in the decision-making. Radical prostatectomy can result in wound infection, hemorrhage, and deep-vein thrombosis, and has a perioperative mortality of up to 1 per cent. In the long term, erectile dysfunction, incontinence, and urethral stricture can also compromise quality of life after radical prostatectomy. For the man whose sexual potency is important or whose risk for complications is great, non-surgical therapies or watchful waiting may be preferred. Newer surgical techniques can minimize periurethral dissection and preserve the erectile nerves, but the impact of radical prostatectomy on sexual function can still be significant. In contrast, the effects of radiotherapy can be much more mild, while watchful waiting has no immediate effects on sexual function or continence. However, radiotherapy and watchful waiting result in a trade-off, where the decreased risk of immediate sideeffects from treatment are exchanged for the increased risk that local symptoms will occur later if the cancer progresses. Watchful waiting In some cases, the risk of cancer progression in the patient's lifetime is so low that no intervention is warranted. Most physicians would agree that this applies to men over 80 years old with localized disease and to men who are over the age of 70 with stage T1a disease. Some European centres also advocate observation for younger men who have well- to moderately differentiated stage T2a and stage T2b disease. Studies on watchful waiting show that T12 disease will have a 10year local progression of 72 per cent, metastasis rates of 23 per cent, and cause-specific eath rates of 8 per cent. (but it must be remembered that most of these men received hormonal therapy at the time of tumor progression). While these rates of progression appear to be similar to those seen with other forms of therapy, these men cannot be directly compared to those who undergo radiotherapy or radical prostatectomy. In general, those assigned to watchful waiting are older, have a lower volume of disease, and lower-grade tumors (some tumors were diagnosed by cytology alone). Furthermore, neither PSA nor prostatic acid phosphatase were

measured over time in these studies, meaning that the actual progression rates of the tumors were probably much higher. Thus, watchful waiting should be applied with caution to men with life expectancies of more than 10 years, with a full disclosure of the risks and benefits of such an approach. External-beam radiotherapy Even more difficult than the decision between treatment and watchful waiting is the choice between surgical treatment and radiotherapy. In most European centres, external-beam radiotherapy is the primary treatment for localized prostate cancer in all men who are less than 80 years old. In North America, it is usually the first choice for treatment only in men who have moderate comorbidity, or who are between 70 and 80 years old. Standard therapy is 5000 cGy over 5 weeks to the pelvis with a further boost to the prostate of 2000 cGy over 2 weeks, although the use of brachytherapy in the prostate is also becoming more commonplace. Radiotherapy can be an effective treatment for many men who have organ-confined (T1/T2) and locally advanced (T3) prostate cancers. Local control for stage T1 and T2 tumors can be achieved in 80 to 95 per cent of patients overall, with 5-, 10-, and 15-year survival rates of 80, 60, and 37 per cent, respectively. While the primary concern in using this treatment for men with a life expectancy above 15 years is the high rate of PSA elevation after treatment, there is no conclusive evidence that surgery offers a significant overall survival advantage over radiotherapy. Radiotherapy does have certain advantages over radical prostatectomy. There is no need for admission to hospital, and the risks of an operation and prolonged postoperative recuperation are avoided. The risks of disabling bladder dysfunction and incontinence are lower with radiotherapy, although impotence can still be a problem over time. However, the side-effects of treatment, the protracted time course of radiotherapy (daily treatments over several weeks), and questions about its efficacy relative to surgical treatment are factors that make it a far from ideal option for all patients. The complications of radiotherapy have been well defined, although variations in dosage, route (external beam versus brachytherapy), and dosage fractionation will affect the rates of complications (Table 4). Proctitis has occurred in up to 30 per cent of patients while undergoing treatment, with 1 to 2 per cent having long-term rectal problems including stenosis or chronic proctitis. Cystitis and gross hematuria are further side-effects that can occur during radiotherapy to the pelvis. Fortunately, most of these irritative voiding symptoms will resolve after treatment, with only 2 per cent of men having severe, long-term problems following external-beam radiotherapy. Erectile dysfunction can also be associated with radiotherapy, with approximately 50 to 66 per cent of potent men becoming impotent

after treatment. However, unlike the erectile dysfunction associated with surgery, the impotence that follows radiotherapy tends to be progressive, and can occur many months to years after the therapy.

Table 4 No caption available.

Surgery In the United States, for men who are under the age of 70 years, who have no significant medical comorbidity, and who have a clinically localized prostate cancer, radical prostatectomy is the primary treatment. Due to (i) the aging of the population, (ii) the advent of PSA-based screening, (iii) the development of transrectal ultrasonography, which makes prostate biopsies easier to perform, and (iv) the major improvements in surgical technique, the use of radical prostatectomy has increased six-fold between 1984 to 1990. However, despite improvements in the ability to detect cancer at earlier stages, and in surgical technique and patient selection, biochemical (PSA-based) recurrence rates after surgery are still between 20 and 30 per cent, with the side-effects (impotence, incontinence) potentially worse than the symptoms that could be caused by the cancer itself. The main issue is the preoperative selection of patients who will best benefit from the surgery, both in terms of cancer control and overall quality of life. Radical prostatectomy is the complete surgical removal of the prostate and seminal vesicles. As originally performed, either by a retropubic or a perineal approach, there was a high incidence of complications, particularly impotence and incontinence. In the early 1980s, better understanding of the neuroanatomy of the pelvis allowed for the preservation of the periprostatic neurovascular bundles responsible for erection (Fig. 2 and Fig. 3). Improved attention to anatomical detail and further modifications in surgical technique have resulted in further improvements in intraoperative blood loss, and in postoperative continence and sexual function.

Fig. 2. Surgical anatomy of the prostate gland with demonstration of the neurovascular bundles.

Fig. 3. Radical prostatectomy, division of lateral pedicles. Note preservation of neurovascular bundles.

Most series report 5-year disease-free survival rates of between 60 to 80 per cent following radical prostatectomy, with the probability of cancer control related to tumor stage. Between 80 and 90 per cent of patients who have organ-confined cancer, 75 per cent who have T3a/T3b tumors, and 10 to 20 per cent who have pathological T3c lesions, will remain free of recurrence 5 years after surgery. The risks of surgery must also be considered as they represent a much greater challenge to the patient than with radiotherapy. As outlined earlier, the short-term complications of radical prostatectomy include stricture, rectal injury, wound infection, and deep-vein thrombosis. Early studies reported varying incidences of these complications but the more recent series clearly show that the incidence of significant, short-term complications is low, owing to improvements in surgical technique (Table 5).

Table 5 Early complications of radical prostatectomy

Over the long term, postoperative impotence can be a significant problem, and it can occur even if both of the erectile nerves were successfully preserved during surgery. Besides the ability to save the nerves, the preservation of potency is mainly dependent on the age of the patient. Postoperative potency rates of up to 80 per cent have been seen in patients who were 50 to 60 years old, while the rate drops to 50 to 60 per cent in men who were 60 to 70 years old. In contrast, men who were over the age of 70 at the time of surgery were rarely potent following radical prostatectomy. Another potential long-term complication is urinary incontinence. Most modern surgical series report that approximately 20 per cent of patients who undergo radical prostatectomy will develop stress urinary incontinence, with less than 1 per cent having severe leakage. Comparison of radiotherapy with radical prostatectomy The side-effects and long-term complications of radiotherapy and radical prostatectomy have been well characterized, but it has been impossible to compare directly the efficacy of these treatments, as the populations who receive them are usually not comparable. Historically, patients who underwent radiotherapy tended to be older and had more locally advanced tumors. Surgery and radiotherapy have also been difficult to compare because studies on the outcome of radiotherapy have always been based on clinical stage, while those on surgery have been based on pathological stage. However, the tendency of the surgeon to underestimate the clinical disease stage is somewhat counterbalanced by a similar tendency for the radiotherapist to overestimate the clinical extent of the tumor. Clinical trials to compare the efficacy of radiotherapy and surgery have been started, but as yet they have not provided definitive answers to this controversy. In comparable groups of men who underwent either radical prostatectomy or radiotherapy, biochemical recurrence rates (as defined by a detectable PSA in the radical prostatectomy group or a rising PSA after radiotherapy) appear to be similar for the first 5 years after treatment. While the evidence so far suggests that the short-term results of radiotherapy and surgery are equivalent, the longer-term results are not yet available. In contrast, some studies with longer-term follow-up suggest that cancer control might not be as good with radiotherapy as it is with surgery. The only completed randomized trial to date that compared the two treatments (from the United States Veterans Administration Co-operative Research Group) favoured radical prostatectomy,

although it had methodological flaws that limited acceptance of its results. A subsequent study also showed a long-term, disease-free survival advantage for surgical patients over those who received radiotherapy, noting that 22 per cent of the former and 39 per cent of the latter had PSA progression. A structured review of the relevant literature also suggested that long-term PSA recurrence rates are higher in patients treated with radiotherapy than in those treated with radical prostatectomy. In patients who had had more than 15 years of follow-up, the biochemical (PSA-based) relapse-free rates ranged between 19 and 46 per cent in the radiotherapy group, and between 40 to 75 per cent in the radical prostatectomy group. Thus, while it is unknown whether or not radiotherapy can control prostate cancer as effectively as radical prostatectomy, the long-term data seem to slightly favour surgery. It is hoped that studies from the Prostate Outcome Research Team (PORT) will clarify this controversy in the near future, as they compare the outcomes of different treatment approaches while trying to control for tumor stage, tumor grade, patient age, and comorbidity. Until these studies have been completed, patients must be given all three options for therapy, with the decision largely based on their preference. Summary In general, the approach we use is as follows. For men who have an expected lifespan of less than 5 years (i.e., those more than 80 years old), watchful waiting is recommended. For those who have a 5- to 10-year expected lifespan, external-beam radiotherapy is recommended, as it can give similar results to surgery with fewer complications. For those who are under 70 years old with an expected lifespan of more than 15 years, surgery is likely to give superior results, although the overall survival benefit will probably be small. In those who have clinical stage T3 disease and a very high risk of metastatic cancer, radiotherapy in combination with hormone therapy might be the best option (see below). Treatment of metastatic disease Hormonal therapy The favourable response of prostate cancer to androgen ablation was first described by Huggins in 1941, and it has remained the treatment of choice for metastatic disease. Over 90 per cent of men with metastatic prostate cancer will have a measurable response to endocrine therapy. While androgen-deprivation therapy is not curative, the mean duration of response is approximately 3 years, with some having a much longer response. The testicles produce about 95 per cent of the circulating androgens under the central control of the pituitary gland and hypothalamus (Fig. 4). The adrenals supply the remaining 5 per cent, although it is

uncertain whether adrenal androgens alone can support the growth of prostate cancer cells.

Fig. 4. Endocrine control of prostate growth via androgen production, and pathways blocked by hormone treatments to control prostate cancer. LH, luteinizing hormone; LHRH, luteinizing hormone-releasing hormone; FSH, follicular-stimulating hormone; DHT, dihydrotestosterone; ACTH, adrenocorticotrophic hormone; CRH, corticotropin-releasing hormone.

There are many forms of endocrine manipulation that can be used to treat metastatic prostate cancer. Clinically, androgen ablation can be achieved by interfering with any step of androgen production or action, from blocking the action of the hypothalamicpituitary axis to stimulate testosterone production to blocking the interaction between testosterone and its receptor (Fig. 4). While there used to be controversy about the optimal use of endocrine therapy, recent studies have provided information that can help both patients and clinicians. The choice of early rather than delayed therapy, the use of total androgen ablation or ablation of testicular androgens alone, and the choice of the therapeutic agent have all been the focus of a research effort, with answers now becoming apparent. The traditional choices for the patient who needs to undergo androgen-deprivation therapy include bilateral orchiectomy, estrogens, luteinizing hormone-releasing hormone (LHRH) agonists, and steroid receptor-blocking agents. Given that each approach has advantages and limitations, the individual's choice has to be based on his ability to comply with the regimen, its simplicity, the safety and side-effects of the treatment, his ability to accept the treatment, its efficacy, and its cost. Orchiectomy Since the original report by Huggins, orchiectomy has been the gold standard' for androgen-deprivation therapy. With orchiectomy, one can achieve rapid and effective reductions in serum testosterone, leaving only the small contribution made by the adrenal glands. Castrate levels of testosterone can be found within 3 h after surgery.

The main advantages of bilateral orchiectomy are that it is safe, effective, inexpensive, and that it can rapidly decrease the serum testosterone. For the most part, bilateral orchiectomy can be done under local anesthesia, with an overall cost for the entire procedure of approximately $3000 (in the United States). As it is a one-time treatment, no further costs are incurred by the patient. Orchiectomy also has advantages where compliance is a problem, or where access to a health-care provider is limited. The main side-effects of orchiectomy are related to the loss of testosterone, including gynecomastia, impotence, and hot flushes. Other problems include surgery-related complications (hematoma, wound infection), loss of self-image, and irreversibility. However, despite these considerations, cost-based analyses have clearly shown the superiority of orchiectomy for the majority of men who have metastatic prostate cancer. Based on British data, assuming an equivalent efficacy between orchiectomy and LHRH agonists, for patients who have a response that is less than 2 years' duration, the LHRH agonist was more costeffective, but for those who have more than 2 years' response, bilateral orchiectomy was more cost-effective. While this study could be faulted because of the high cost and 5-day hospital stay for orchiectomy, and the relatively cheapness of the chosen LHRH agonist, it is clear that orchiectomy was the most cost-effective approach for the majority of those with metastatic prostate cancer. Estrogens Exogenous estrogen is believed to block androgen metabolism and the growth of prostate cancer at several levels: feedback inhibition of the hypothalamicpituitary axis, direct suppression of testicular androgens, increased concentrations of sex steroid-binding globulins and prolactin, and direct suppression of tumor growth. To date, the most widely used agent has been diethylstilbestrol at doses of 3 to 5 mg/day. While 1 mg/day is ineffective, the majority of men will have a castrate concentration of testosterone at 3 mg/day, with some requiring 5 mg/day. The main advantages of diethylstilbestrol are its low price (approximately $100 per year in the United States), its effectiveness in achieving the castrate state and as an anticancer agent, and its simple dosing schedule. Unfortunately, the incidence of life-threatening side-effects increases with increased dose. In addition to the standard side-effects of androgen-deprivation therapy, diethylstilbestrol has also been associated with an increased risk of gynecomastia, thromboembolic phenomena, cardiovascular complications, and sudden death. In fact, once the costs of breast irradiation and those incurred for the treatment of diethylstilbestrol-associated cardiovascular complications are included, the cost advantage for diethylstilbestrol is lost. Furthermore, at a dose of 5 mg, the survival benefit that is due

to the hormone treatment of the cancer is lost because of the increased cardiovascular morbidity that is secondary to it. Thus, given the side-effect profile and the existence of less toxic and equally effective hormonal agents, diethylstilbestrol has become a treatment of historical import only (this is especially true because it is no longer available in most countries, owing to the lack of manufacturers willing to produce this inexpensive but potentially toxic agent). LHRH analogues LHRH analogues result in a flare of testosterone after about 3 days, with it then paradoxically dropping to castrate concentrations within 2 weeks through downregulation of pituitary receptors and depletion of luteinizing-hormone stores. The clinical effect is equivalent to orchiectomy or diethylstilbestrol, although somewhat delayed. LHRH agonists (such as leuprolide or goserelin acetate) have become the mainstay of androgen-deprivation treatment in the United States. These produce a lower incidence of gynecomastia and fluid retention but a higher incidence of hot flushes than the estrogens. In addition, unless the early flare' period is covered by diethylstilbestrol or an antiandrogen, there is a danger that the tumor will be stimulated in the first 2 weeks of treatment, leading to an exacerbation of symptoms including urinary retention, spinal-cord compression, and pain from skeletal metastasis. LHRH analogues are available as daily subcutaneous injection, as a nasal spray, as a monthly depot injection, or as an implant that lasts 3 months. The main advantages of LHRH agonists are their safety, their reversibility (if intermittent androgen-deprivation therapy is to be considered), and their effectiveness in achieving castrate concentrations of testosterone. However, LHRH agonists are also associated with significant inconvenience and cost: regular visits to the doctor are required for the injections, compliance with the regimen can be problematical where access to the health-care provider is limited, and finally, the cost of the medication itself can be prohibitive. In US dollars, the LHRH agonist will cost each patient approximately $5000 per year, or $12 500 for the entire course of therapy (assuming a median survival time of 30 months for the patient with metastatic prostate cancer). Based on the entire cost of an orchiectomy, the break-even point for cost in the United States between orchiectomy and LHRH agonist is at 6 months, after which LHRH agonists become more expensive. Total androgen blockade The goal of total androgen blockade is to block the effect of both testicular and adrenal androgens. Typical regimens have combined either orchiectomy or LHRH analogues with a pure antiandrogen

(such as flutamide or bicalutamide). The early results were promising. The American National Cancer Institute study that compared an LHRH analog with or without flutamide showed a statistically significant increase in time to progression and a reduction in mortality rate if total androgen blockade was used, although the overall improvement in survival was only 3 months. Similar results were found in a Canadian trial that showed an overall improved survival of 5 months. Subset analysis in both of these studies suggested that patients with a low burden of disease and good performance status benefited most from total androgen blockade. A cost analysis also suggested that the use of total androgen blockade is reasonable. Given that antiandrogens cost approximately $10 000 per year (in the United States), it was estimated that total androgen blockade costs between $13 000 to $48 000 per life-year saved, depending on how much of a survival benefit was expected from it. Since dialysis costs approximately $40 000 per life-year saved, the argument was made that the cost of total androgen blockade is similar to that of other, well-accepted medical interventions. However, despite these initially promising results, more recent studies suggest that the utility of total androgen blockade is much more limited. In a large, randomized, prospective study of orchiectomy compared with orchiectomy plus antiandrogen, no differences in overall survival were seen. Subset analysis failed to identify any subgroup that benefited from total androgen blockade. These results, in combination with the high cost of antiandrogen therapy, have basically put to rest the concept of total androgen deprivation. Other hormonal agents Ketoconazole Ketoconazole is an imidazole derivative that inhibits cholesterol metabolism, resulting in ablation of both testicular and adrenal androgen production. It is the most rapidly acting medical treatment for androgen ablation, with castrate concentrations of testosterone achieved within 8 h. Primary side-effects are nausea, gynecomastia, impotence, pruritus, liver dysfunction, and adrenal insufficiency; therefore, ketoconazole is often given together with hydrocortisone. This medication is extremely useful in the patient who needs emergency therapy (such as in impending spinal-cord compression), given its rapid onset of action. A second condition in which ketoconazole appears to be useful is for the patient who is failing in first-line hormone therapy: there are now anecdotal reports of durable PSA responses in men who have prostate cancer that is

progressing despite previous orchiectomy or treatment with an LHRH agonist. Glucocorticoids Prednisone at a dose of 15 mg/day can decrease PSA in castrate men, with a reported 20 per cent objective improvement in symptoms. Whether this effect is due to effects on testosterone or on inflammation around the tumor is unclear. Treatment of the complications of metastatic prostate cancer Spinal-cord compression This devastating complication must always be considered in patients with prostate cancer who have back pain or decreased sensation in lower limbs. The finding of cord compression should be considered an emergency: patients who have pain or paraesthesia can often recover function if they are treated promptly, while those who present with paralysis rarely recover function after treatment. Given that patients with metastases can live for many months, preservation of function is of critical importance for the preservation of qualityof life. Spinal-cord compression should be suspected in any patient who is having progressively worsening back pain, sciatica, weakness in the lower extremities, or urinary/fecal incontinence. Once suspected, the diagnosis can be confirmed by MRI: because of the high incidence of diffuse spinal involvement, it is important to image the entire spine and not just the area that is symptomatic. Treatment usually involves emergency neurosurgical consultation, high-dose steroids, and either external-beam radiation or decompressive laminectomy. Urinary obstruction Local extension of prostate cancer is sometimes found at the time of diagnosis, or may occur after external-beam radiotherapy. Obstruction of bladder outflow can present with hesitancy, dribbling, straining, slowing of the urinary stream, or urinary retention. The ureters can also become obstructed either due to the local extent of the primary tumor along the trigone or to extrinsic compression from involved retroperitoneal lymph nodes. Management of urinary-tract obstruction will depend on its degree, the severity of symptoms, and the prior treatment that the patient has received. For the man who has mild voiding symptoms from prostate cancer, or who has unilateral ureteral obstruction but otherwise normal renal function, either observation or endocrine therapy can be the primary approaches. In contrast, the man who has significant obstructive voiding symptoms, or recurrent gross hematuria, should undergo a limited transurethral resection of the prostate to alleviate his discomfort.

Likewise, the man who has a reasonable life expectancy and bilateral ureteral obstruction should also be treated, using either antegrade or retrograde ureteral stenting to stabilize renal function. The stents can usually be removed in 2 to 3 months, once endocrine therapy has adequately reduced the size of the tumor. In contrast, for the man who has developed ureteric obstruction while on androgen-deprivation therapy, the prognosis is grim and caution should be used before any intervention. Comparative studies have shown that procedures to unobstruct the kidneys in the presence of a hormone-refractory prostate cancer do not improve quality of life or increase overall life expectancy. Thus those who have ureteral obstruction and hormone-refractory prostate cancer need to be counselled for their poor prognosis, with consideration given to hospice care without any further invasive surgery. Likewise, for the man who has progressive, hormone-refractory prostate cancer and urinary retention, prostatic stents, urethral catheterization or a suprapubic tube can be used to drain the bladder until he succumbs from his disease. Bone pain For most patients who have isolated, symptomatic bone metastasis, external-beam radiotherapy can be used to palliate symptoms. For those who have metastatic disease in the spine, radiotherapy can also be used to stabilize the axial skeleton and prevent the later occurrence of spinal-cord compression. For those who have more diffuse symptomatic skeletal disease, systemic radioactive agents such as strontium-89 can be used, resulting in a significant decrease in pain scores and the need for narcotics. Unfortunately, this therapy is associated with bone-marrow suppression and has only minimal long-term efficacy. Aggressive pain management should also be instituted, as the patient who has advanced prostate cancer can live for quite some time. An approach that is similar to the World Health Organization Pyramid should be used. Acetaminophen (paracetamol), non-steroidal antiinflammatory agents, and oral narcotics are usually the initial steps for outpatient pain management, and should provide adequate relief for the majority of patients. For those who have more severe symptoms, consultation from a cancer pain-clinic team should be obtained for therapy that is based on neuroleptics, narcotic patches, epidural implants, and nerve blocks. Recommended treatment by stage The following are our own recommendations and represent an approach that, in 1998, would be considered somewhat conservative in North America and aggressive in Europe. Each treatment choice is recommended to the patient as our own preference: but all treatment

options with their risks, benefits, and the strength of the data supporting them are given as alternatives. Some of the information given here repeats and reinforces the account given above. Clinical stage T1a and T1c Treatment decisions for the man who has T1a prostate cancer must be based on confirmation that he has a small, low-grade tumor. Our current policy is to perform repeat transrectal ultrasound biopsies in those who have stage T1a tumors, unless they have been poorly resected, in which case a repeat transurethral resection plus a needle biopsy is appropriate. If the resampling is negative, then patients can be followed serially with digital rectal examination and PSA testing at 6-month intervals, with any significant change in either signalling the need for further biopsies. In contrast, if, on re-evaluation, the patient has a more significant tumor, then treatment decisions need to be based on his age and general medical condition. Similarly, the management of those who have clinical T1c tumors must be influenced by their age and the tumor grade. As almost all stage T1c tumors are clinically significant (either high-grade or of significant volume), and as many are in fact pathologically much more advanced than anticipated from the digital rectal examination (with involvement of periprostatic fat in 44 per cent and extension into the seminal vesicles in 8 per cent), we generally recommend definitive treatment for almost all younger men who have a T1c tumor, even if they only have a single focus of well-differentiated tumor found on a single biopsy core. In contrast, for those who are older, or where there is a question about their 10-year life expectancy, we tend to be more conservative provided that a second set of extensive biopsies, including deep transition-zone biopsies, shows no significant tumor volume and no tumor with a grade greater than Gleason 3. Clinically organ-confined (stage T2) With the diagnosis of a stage T2 prostate cancer, the treatment decision can be difficult. The standard choices include radiotherapy, radical prostatectomy, and watchful waiting, but, as discussed earlier, the final choice cannot be based on any firm scientific evidence that one form of treatment is better than another. Therefore, decisions have to be based more on the side-effects, long-term risks, and financial and emotional costs of the different therapies. In general, young healthy patients have historically been steered towards adical prostatectomy in the United States, while older patients are steered towards observation or radiotherapy. This is due to the different risks and benefits that have been associated with radical prostatectomy, radiotherapy, and observation. For men who are in good medical condition and are under the age of 70, radical prostatectomy is commonly recommended, although the

evidence supporting this approach over radiotherapy is extremely limited. With improved patient selection, anesthetic technique, and hospital care, the surgical complications are minimal, with the average hospital stay following radical prostatectomy decreased to 3 days. In most cases, the patient is able to eat a regular diet within 2 days of surgery, with full activity resumed within a month. As there is no apparent difference in cure rates between surgery and radiotherapy, the choice for surgery has to be based on other criteria. The main differences between radiotherapy and surgery for treating prostate cancer are the more accurate staging information and the higher risks of long-term, treatment-related complications from surgery. With radiotherapy, tumor stage is established on the PSA and digital rectal examination, both of which are poor predictors of actual tumor volume. Furthermore, up to 40 per cent of patients are found to have been undergraded when the results from the needle biopsy are compared to the Gleason score of the final specimen. Thus, the actual tumor grade and stage remain unknown for the patient who undergoes radiotherapy, with that information only inferred from the response to treatment. In contrast, following radical prostatectomy, more accurate prognostic information can be given, and high-risk patients who would benefit from adjuvant therapy can be identified. However, this improved prognostic information comes at the cost of a higher risk for the patient. While radiotherapy is not associated with the involuntary loss of urine, most current series report that approximately 20 per cent patients who undergo radical prostatectomy will have some degree of stress urinary incontinence after surgery, with approximately 1 per cent having severe leakage. Postoperative impotence can also be a more common problem after radical prostatectomy. While the technique of peeling the erectile nerves off the lateral edge of the prostate has markedly improved the outlook for adequate sexual function, the return of normal erections also depends on the preoperative sexual function and the patient's age. In general, younger men have a better chance of preserved potency if they are treated by radical prostatectomy with nerve sparing, while older men have a better chance of preserved sexual function after radiotherapy, as nerve sparing rarely works once the patient is over the age of 70. Radiotherapy has other advantages over surgery. It is well tolerated, not associated with hemorrhagic or anesthetic risks, and does not require admission to hospital or a significant recovery period. Normal activity can usually be maintained during radiotherapy, although daily visits to the radiotherapist are required for 4 to 6 weeks, and many patients do report feeling fatigued at the end of the treatment programme. However, radiotherapy also has disadvantages compared to surgery. Aside from some uncertainty about the success

of the treatment, radiotherapy can have significant side-effects. While incontinence is not associated with radiotherapy, severe bladder irritation (urgency, pain and frequency) can occur in 5 per cent of patients. Furthermore, rectal irritation (diarrhea, rectal urgency, tenesmus, and rectal bleeding) can occur in 3 to 10 per cent of patients, with impotence occurring in 40 to 50 per cent. And finally, over the long term (greater than 10 years), radiotherapy may not provide as good a chance of cure as surgery. After radical prostatectomy, the majority of recurrences are within the first 4 years, while for radiotherapy, recurrences can arise over a much longer period of time since the prostate may not have been completely ablated. Thus, while cure rates for radiotherapy and surgery appear to be equivalent at 5 years, these results may not hold up over longer follow-up. In summary, there is no single, best treatment for organ-confined prostate cancer. Until definitive data are collected that prove in a randomized, prospective manner that one approach is superior to the other, the treatment choice has to individualized to the patient's goals for health maintenance, and to his age and the presence of other illness. Until there are believable data on efficacy, watchful waiting, radical prostatectomy, and radiotherapy (including brachytherapy) can all be considered acceptable treatment options, with the differences in side-effects determining when they are to be used. Locally advanced: stage T3 There is no consensus on the optimal treatment for men who have locally advanced prostate cancer. Decisions about the management of the patient with T3 prostate cancer must be based on the known prognostic factors that predict his overall life expectancy and determine the risk of tumor progression. As up to 50 per cent of patients who have a clinical T3 lesion will have lymphatic metastases at the time of surgery, as therapy of any kind is rarely curative, and as surgery overall is not provenly superior to radiotherapy in the management of these tumors, the treatment for the man who has locally advanced prostate cancer can involve androgen-deprivation therapy alone, surgery, radiotherapy, or a combination of these. For T3 disease, surgery or radiation alone are rarely curative. Recurrence rates after treatment can be as high as 80 per cent, with approximately 50 per cent of patients having positive nodes, and 2 per cent invasion of the tumor into adjacent organs. Therefore, therapies that combine systemic hormonal manipulation with local treatment of the primary tumor have been devised. Neoadjuvant hormone therapy has not improved the chance of longterm cure after surgery, but might have some benefit for those treated with radiotherapy. Radiation therapy alone was associated with an overall, clinical disease-free, and PSA disease-free, survival of

71, 43, and 26 per cent, respectively, while the comparable proportions for the group that received neoadjuvant hormones were 84, 61, and 46 per cent. Whether or not this beneficial response will translate into improvements in overall survival is unknown. Alternative strategies for T3 prostate cancer include cryotherapy (freezing the prostate with liquid nitrogen), a combination of externalbeam radiation with brachytherapy (therefore allowing the administration of higher radiation doses to the prostate), or combinations of standard therapies with gene treatments that try to enhance a tumor's sensitivity to the immune system. Hormone-sensitive, metastatic disease (N+, M+) Prostate cancer classically spreads to the bones and lymph nodes: in such patients, androgen-deprivation therapy is the mainstay. However, with the definition of an entire population of men who have metastatic cancer based on the serum PSA and yet have no symptomatic or radiological evidence of malignancy, the timing of, and indications for, androgen-deprivation therapy have become controversial. Preliminary data had suggested a survival benefit for immediate rather than delayed androgen-deprivation therapy (where treatment is offered only when symptoms appear), but flaws in study design limited the strength of this conclusion. For example, a recent study from Great Britain that showed a survival benefit for early as compared to deferred androgen-deprivation therapy basically compared patients who had had immediate treatment with a group that had received no treatment at all. There are other randomized, prospective studies that have failed to show a survival benefit for early androgen-deprivation therapy. Given the lack of conclusive data, patients who have asymptomatic, metastatic disease should be offered the choice between early or delayed endocrine therapy. While there are potential (and unproven) survival benefits for those who undergo early hormonal therapy, the patient must also understand that the treatment is associated with significant side-effects, including osteoporosis, loss of libido, impotence, hot flushes, malaise, and gynecomastia. In contrast to the asymptomatic, symptomatic patients should receive immediate endocrine therapy since they can then see a rapid improvement in their symptoms. In emergencies (such as impending spinal-cord compression), bilateral orchiectomy or ketoconazole therapy should be instituted, as these can result in the most rapid decline in serum testosterone. For other patients, the choices include total androgen deprivation, bilateral orchiectomy alone, or a depot LHRH analog alone. Bilateral orchiectomy is the simplest and least expensive of the options, and has the advantage that monthly visits to the physician for injections are not required (especially important where access to the provider is

limited, or where the patient has a history of non-compliance). On the other hand, acceptance of orchiectomy has been problematical in some populations for cultural reasons, with the use of LHRH agonists representing the primary mode of androgen-deprivation therapy in the United States. LHRH agonists and orchiectomy are equivalent in their ability to reduce the serum testosterone. The main differences between the two are related to (i) reversibility, and (ii) cost. Intermittent hormone ablation has been used to treat advanced prostate cancer in some patients. In this approach, LHRH agonists are used cyclically, with times where the patient is off of the medication. This approach can be advantageous to the patient who wants to minimize side-effects, as sexual function and energy can return to normal during those times. For those treated with LHRH agonists, intermittent therapy is an option. For those treated by orchiectomy, the loss of testicular androgens is permanent. However, it must also be remembered that the long-term efficacy of intermittent androgen deprivation has yet to be proved, although animal studies suggest that this approach will not decrease the amount of time that a patient will respond to androgen-deprivation therapy. The other consideration is financial. Given the need for cost containment in modern medicine, and given the identical efficacy of orchiectomy and LHRH agonists, in most circumstances surgical castration should be the preferred method for androgen deprivation because it is cheaper. As 95 per cent of testosterone production comes from the testicles and 5 per cent from the adrenal glands, there was concern that the relatively small amount of adrenal androgens could promote growth of the cancer. Because of this fear, the concept of total androgen blockade was developed, where orchiectomy or an LHRH analog are used to ablate testicular androgen production, while an androgenreceptor blocker (flutamide or bicalutamide) is used to eliminate the effect of the adrenal androgens. While preliminary evidence showed improved survival for patients treated by total androgen blockade, later prospective, randomized trials failed to show any survival benefit. In addition, the cost of antiandrogens can be prohibitive, running up to US$15 000 per year. Hormone-refractory disease There has been a recent reconsideration of the term hormone refractory,' given that many patients who fail a first-line hormonal manipulation will often respond to a second or even a third. With this understanding came a modification in nomenclature, as (i) it has been argued (see above) that the low concentrations of testosterone coming from the adrenal glands may also be contributing to the growth of the cancer, and (ii) that the antiandrogen medications in common use (flutamide, bicalutamide) may actually develop agonist

properties that can stimulate cancer growth as the tumor progresses. For patients who have androgen-resistant but hormone-sensitive tumors, this implies that the ablation of testicular androgen production alone is no longer effective. In such men, the addition of an antiandrogen to block the testosterone receptor (e.g. flutamide or bicalutamide), or the discontinuation of the antiandrogen (if the patient is already on one) may be able to induce a transient response. While there are few data on the initiation of an antiandrogen at the time of tumor progression, the antiandrogen withdrawal phenomenon has been well described, in which stopping the antiandrogen results in tumor regression that can last for 3 to 6 months in approximately 33 per cent of patients. The other option for the hormone-sensitive but androgen-insensitive patient involves the use of steroids in combination with ketoconazole (ketoconazole is a potent inhibitor of adrenal steroid production). Therapy combining ketoconazole and hydrocortisone can produce significant decreases in serum PSA and cancer symptoms in a small subset of patients. While one of the mechanisms of ketoconazole involves the suppression of adrenal androgen production, a direct cytotoxic effect is probably important as well. Unfortunately, most of these secondary interventions for metastatic prostate cancer are only effective for 2 to 3 months, after which the tumor begins to grow again. At this point, the patient should be considered to have hormone-refractory disease (i.e., both androgenand hormone-resistant). For the atient who is young and has a good performance status, enrolment in a chemotherapy trial should be considered if one is easily available. For other patients, hospice care should be considered. Until recently, prostate cancer has been considered to be a chemoresistant tumor. However, with the recent development of new chemotherapy agents and with a better understanding of the molecular biology of prostate cancer, there are new pharmacological manoeuvres that can induce short-term responses in patients who have hormone-refractory prostate cancer. PSA-based response rates ranging from 50 to 60 per cent have been seen for chemotherapeutic agents such as paclitaxel, docetaxel, and vinorelbine. While these PSA responses have not yet resulted in any improvement in overall survival, these treatments should still be considered valuable, as improved functional status and subjective improvement in cancer pain can be seen after chemotherapy. Where the patient is too debilitated to undergo chemotherapy, palliation of symptoms alone should be the goal of treatment. As most patients with hormone-refractory prostate cancer can live for many months, the preservation of function is critical for the maintenance of their quality of life. In cases of urinary retention, a limited transurethral resection is reasonable; otherwise consideration

can be given to inserting a chronic indwelling catheter. For patients with ureteral obstruction secondary to lymphadenopathy, nephrostomy tubes or internal stents can be placed for drainage, although most of these men will have a very short life expectancy and will not benefit from aggressive attempts to preserve renal function. For the patient with prostate cancer metastatic to the skeleton, adequate pain control must be ensured through the use of antiinflammatory medications and narcotics (see earlier). Systemic strontium or spot radiotherapy treatments can also be effective in some cases to improve pain control. In addition, vigilance must be maintained for the symptoms of spinal-cord compression (such as sudden changes in gait, or a sudden change in bowel or bladder habits), as many men who have advanced prostate cancer have a significant lifespan to come despite their hormone-refractory state: the detection and active treatment of unstable spinal segments will allow them to remain ambulatory and functional for as long as possible.