1.1 Prostate cancer in Singapore

Prostate Cancer is the 6th commonest cancer among men in Singapore*. While the incidence is substantially lower than that in many Western countries, it has been increasing even having corrected for life expectancy. Furthermore, the majority of patients with prostate cancer presents with locally advanced and/or metastatic disease at the time of first diagnosis. The prognosis of advanced prostate cancer is poor despite the most aggressive treatment. Cure is impossible for metastatic prostate cancer; median time to progression and median survival is approximately 18 and 30 months respectively. Such data contrast sharply with the results of treatment for localised disease. Median survival has been shown to be longer than 15 years. The observed crude survival rates were identical to the expected survival of age-matched controls. As such, it is reasonable to strive for early diagnosis and treatment in the hope of survival benefits. However, uncertainties of the natural history of the disease and efficacy of treatment due to the lack of randomised control studies still cast doubts on the potential benefits of an early screening programme.

* Trends in cancer incidence in Singapore 1968-1992, Singapore Cancer registry

1.2 Guideline development and target group

Workgroups, comprising members of the Singapore Urological Association and the Asian Society for Uro-oncology were formally appointed by the National Cancer Centre Committee to formulate the clinical practice guidelines on urogenital cancers. One of the workgroups embarked on developing guidelines on management of prostate cancer and presented the draft to a panel of international and regional experts. All the relevant issues were thoroughly discussed till a broad consensus was achieved.

These guidelines are prepared for clinicians who may be interested in the care of patients with prostate cancer. The guidelines cover a wide range of issues; some of them may not be immediately relevant to subspecialty practitioners while others remain as issues for future research due to the paucity of evidence in the literature. Revisions would be necessary when new evidence is available.

More information on the topic is available on the following websites.
http://www.cancernetwork.com/indexes/nccn.htm
http://cancernet.nci.nih.gov/clinpdq/soa.html

Levels of evidence

Grades of recommendation

Screening and diagnosis

A Population screening for prostate cancer among Asians should not be recommended. (Ia/A) Grade A, Level Ia

The appropriate threshold PSA level for case detection is 4.0 ng/ml. (IIb/B)

Combination of digital rectal examination and PSA enhances early detection. (IIa/B)

Other imaging modalities including Transrectal Ultrasonography (TRUS), Computed Tomography (CT) scan and Magnetic Resonance Imaging (MRI) have limited value in diagnosis and staging.

• A Volunteers and/or referred patients with abnormal PSA results and/or suspicious DRE are recommended to undergo prostate biopsy. (Ib/A) Grade A, Level Ib
• There may be a role of CT/MRI in the staging of patients with high risk of nodal metastasis (III/B)

Treatment

The choice of treatment of localized prostate cancer between surveillance, surgery and radiation should be individualized based on assessment of the biological potential of the disease, the life expectancy of the patient and the preferences of the patient. There is no clear-cut evidence available showing definite advantage of one over the others.

• The absence of complications compared to conventional radiotherapy or radical surgery and the minimal costs involved are the potential benefits of surveillance in patients with low-grade, low volume tumour and elderly patients with limited life expectancy. (III/B)
• The patient most likely to benefit from surgery would have a clinically organ-confined disease, a relatively long life expectancy, no significant surgical risk factors and a preference to undergo surgery. Radical prostatectomy should be considered in particular for the high-risk group (i.e. Gleason's sum > 6, stage T2c or PSA < 20 ng/dl). (III/B)
• Long term results of radiotherapy in stage T1 and T2 patients are similar to those reported with radical prostatectomy despite differences in case selection and the lack of surgical staging of the lymph nodes in most cases. (III/B)
• Hormonal therapy remains the mainstay of treatment for metastatic prostate cancer. Surgical castration is equal in efficacy compared with other means of medical castration including total androgen blockage. (Ib/B)
• None of the second-line treatment options has shown consistent advantage. The choice of treatment should again be individualized.

4.1 Screening

Although some guidelines advocate annual digital rectal examination (DRE) and prostate specific antigen (PSA) test for men above 50 years of age, there is currently insufficient scientific evidence to show a correlation in decrease mortality from prostate cancer by screening. (1 - 4)

At present, screening is not recommended among Asians. (A/Ia) However, all males above 40 years of age with the risk factor of having a first degree relative with prostate cancer at young age (<60 years) may be screened. (GPP)

4.2 Diagnosis

Patients usually only develop symptoms in advanced stages of the disease. The majority of cases of early prostate cancer are diagnosed incidentally at transurethral resection of the prostate for benign prostatic hypertrophy (BPH) or by individualized testing.

4.3 Tests for screening and diagnosis of prostate cancer

Prostate Specific Antigen (PSA)

• PSA is the most useful test in the detection of prostate cancer in Western countries. The value in Asians compared to DRE and TRUS is less clear partly because of the lower incidence of prostate cancer in the population. (5, 6) The appropriate threshold PSA level for detection of cancer of the prostate is 4.0 ng/ml. (7 - 10) Clinically significant cancers are detected by PSA testing. (B/IIa) (4, 8, 11) PSA-based screening has induced a stage migration, (4, 13) but only very preliminary indications of improved survival is available. (C/IV) (7)
• Age-specific PSA ranges were devised to improve the detection of clinically significant cancer for the younger patients and improve specificity in the older ones. However, the improved sensitivity and specificity is at best modest and hence not recommended. (12, 14)
• PSA velocity (0.75ng/ml/yr) has not improved the sensitivity and specificity of the test and is probably not useful as first line assessment for cancer of prostate. (15, 16)
• PSA density is not recommended as there is no improvement in the sensitivity and specificity over the PSA level. (17 - 20)
• Ratio of free to total PSA levels is recommended as the sensitivity and specificity of PSA levels at 2 -10ng/ml for detecting cancer of the prostate is higher. (B/IIa) However, the optimal cut-off level is still being investigated. (21 - 23)

Digital Rectal Examination (DRE)

• DRE is recommended as the combination of DRE and PSA test enhances early prostate cancer detection. (B/IIa)

Transrectal Ultrasound Guided Biopsy (TRUS)

• Volunteers and/or referred patients with abnormal PSA results and/or suspicious DRE are recommended to undergo prostate biopsy. (A/Ib) (4, 6)
• The standard sextant technique of needle biopsy uses a transrectal approach under ultrasound guidance (TRUS). More number of cores may be needed if hypoechoeic and/or suspicious lesions are present especially in large prostates. (24) TRUS alone has little value in the definitive diagnosis of prostate cancer.
• TRUS is a safe procedure with few major but frequent minor complications. The use of antibiotics for aerobic and anaerobic coverage is to be considered with little consensus available on the most appropriate regimen. (B/III) (25, 26)
• Prostatic biopsy should be repeated in patients with normal histology but suspicious DRE or persistently elevated/rising serum PSA. (27, 28) Biopsy at additional sites including lesion directed biopsies, lateral peripheral zone biopsies and mid zone biopsies etc. may also increase the diagnostic yield. (28, 29)
• Biopsy finding of high-grade prostatic intraepithelial neoplasia (PIN grades 2 and 3) and invasive prostate cancer necessitates further investigations in patients who are candidates for radical treatment of localised prostate cancer. (B/IIb) (30, 31)

5 Staging of prostate cancer

5.1 Investigations for staging of prostate cancer

Decision-making regarding treatment options are dependent on assessment of the biological potential of the disease, the overall health of the patient and the available treatment expertise. The current staging and grading methods of prostate cancer strive to provide reliable predictor of the aggressiveness of the disease. (Annex 1) However, clinical staging using DRE, imaging methods suffer from lack of specificity. Significant number of patients with clinically localized disease has locally advanced disease at surgery. Though the Partin tables* apply consistently to populations of Asians in predicting organ-confined disease, there is significant under and over staging based on clinical parameters. As such, more tests have evolved to stage the disease accurately before treatment plans.

• DRE - This is not recommended as a precise staging modality as the finding may differ significantly from the actual pathological stage. Concurrent prostatic diseases like BPH, prostatitis, previous prostatic biopsy or surgery could make the assessment more difficult. (B/ III) (32, 33)
• Prostatic Acid Phosphatase (PAP), Alkaline Phosphatase (ALP) are less useful compared to PSA.
• PSA - Serum PSA level of < 10ng/ml indicates a lower risk of peri-prostatic spread and metastasis. An increase risk of extra-capsular extension or seminal vesicle involvement and even distant metastasis may be indicated by PSA level >10ng/ml. As a general guide, if PSA >10ng/ml, more than 50% have capsular penetration; if PSA > 50ng/ml, majority have positive pelvic lymph nodes. (B/ IIb) (34)
• TRUS - TRUS is of limited value for staging of prostate cancer. (36, 37) The increasing number of positive biopsy cores and the presence of perineural invasion have negative prognostic implications. (B/III) (34)
• Pelvic lymph nodes dissection - This remains the most accurate method of assessing nodal metastasis. However, patients with low risk disease (PSA < 10ng/ml, Gleason's sum < 7 and stage T1c disease) have less than 5% chance of having positive lymph nodes. As such, only high-risk patients with stage T3c or node-positive disease should be recommended for pelvic lymph nodes dissection before definitive treatment for localized prostate cancer. (B/IIb) (34, 38)
• Seminal vesicle biopsy - This is not recommended as it does not add significantly to the combination of clinical staging, PSA and Gleason score, which predicts the incidence of seminal vesicle involvement to an acceptable degree. (B/IIb) (34)
• Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) - The current role of CT and MRI in staging of localized prostate cancer is rather limited. Most of the microscopic features of extra-capsular spread, seminal vesicle invasion and pelvic node metastasis are not obvious in radiological films. Inter-observer variation has also been reported. However, there may be a role of CT/MRI in the staging of patients with high risk of nodal metastasis. (B/III) (36) (39) (40 - 42) MRI may also be useful in cases of high clinical suspicion of bone metastases with inconclusive bone scan or probable vertebral pathology leading to a spinal cord problem. (43, 44)
• Bone Scan - This is the most sensitive method for detecting bone metastasis. However, in cases with PSA < 10 ug/L , the probability of positive scan is low in the absence of bone pain. Bone scans can be omitted in these patients. (B/III)

Without a thorough understanding of the natural history of prostate cancer and reliable tools to predict prognosis, patients diagnosed to have prostate cancer should be counselled on the available options including surveillance alone, surgery, radiation or combination of the above. No consensus could be reached on the relative merits of the various treatment strategies in terms of overall mortality and cancer-related mortality. The questions raised by Dr Whitmore still remains unanswered: Is cure necessary when possible and possible when necessary?

The various treatment modalities and the follow-up plans are discussed in the following pages.

6.1 Surveillance

• Current evidence suggests that patients with low-volume, low-grade prostatic carcinoma may be asymptomatic for prolonged periods. 80% of the autopsies of men who died of other causes showed occult prostatic carcinoma. Overall survival of patients with clinically localised prostatic carcinoma were not statistically different from the life-table probability for men of similar age-group. (45, 46) Of those under expectant management for more than 10 years of follow-up, the cause of deaths was not prostatic carcinoma. (47, 48) Surveillance alone has been shown to achieve comparable results with other treatment modalities namely conventional external beam radiotherapy and radical surgery. Most series achieve 80-90% 10-year survival rates after excluding deaths from intercurrent diseases.
• The absence of complications compared to conventional radiotherapy or radical surgery and the minimal costs involved are the potential benefits of surveillance in patients with low-grade, low volume tumour and elderly patients with limited life expectancy. (B/III)
• Follow-up assessment includes 6 monthly consultation with routine DRE and serum PSA (Please refer to section 5). Prostatic biopsy and bone scans may be indicated. (48)
• PSA surveillance is recommended as post-primary treatment follow-up of localised disease. The doubling time of PSA of less than 6 months post-treatment may suggest systemic progression. (35)

6.2 Radical Prostatectomy

With the widespread use of PSA, more patients are found with organ-confined disease and curative measures by surgical removal of the cancer can be achieved. (4, 49) Surgery also offers more accurate staging allowing better planning for adjuvant therapy.

• Assessment of the biological potential of the disease, the life expectancy of the patient, the preferences of the patient and availability of expertise are important considerations in establishing the choice of therapy for localized prostate cancer. (50) The results of non-randomized retrospective reviews showed that 10 and 15 years actuarial survivals are 10-15% better after surgery than radiation or surveillance particularly for the high-risk group, i.e. Gleason's sum = 8, stage T2c or PSA < 20 ng/dl. (B/III) (49) (51 - 55)
• Patients with clinically organ-confined disease, relatively long life expectancy, and no significant surgical risk factors are most likely to benefit from surgery. (56) Young patients in the high-risk group may benefit from surgery. (B/IIa)
• In selected individuals with prolonged life expectancy surgery may be offered to clinically stage T3 disease. (B/III) For patients with stage T1a and T1b disease, surgery is an option for young patients < 70 years of age with intermediate or high-risk disease, e.g. T1b with Gleason's sum 5. The additional morbidity associated with radical prostatectomy after TURP should be considered. (B/III) (58)
• Gross locally advanced disease (e.g. presence of hydronephrosis), failure after radiation and patients with less than 10 years life expectancy are contra-indications to radical prostatectomy. (B/ III) (59, 60)
• As radical prostatectomy carries significant morbidity, a thorough evaluation of the patient's co-morbidity and discussion of options are recommended. (B/III)
• Short-term morbidity includes intraoperative bleeding, rectal injury, pulmonary embolism, myocardial infarction and infective complications. Long-term morbidity include incontinence, impotence and bladder neck contracture. (56) (64, 65) Erectile dysfunction is common even after nerve sparing procedures. (66) Overall morbidity may be higher than that reported from large institutions. (67)
• Intraoperative pelvic lymph node dissection may be omitted in patients with low PSA, low Gleason's score and clinically early disease (B/III) (61, 62) (34)
• Both perineal and retropubic prostatectomy gives comparable results in terms of morbidity and disease free survival. (B/III) (63)
• Neoadjuvant hormone therapy has not resulted in improved survival. (68, 69) (II/B not recommended) Planned adjuvant hormonal or radiotherapy for locally advanced disease prolong disease-free interval, the impact on survival is not clear. The option of adjuvant/salvage therapy should be considered after failed definitive therapy. (70) Some series have reported good long term results for patients with locally advanced disease after surgery and adjuvant hormonal therapy. (57)
• PSA levels should be taken at 4-6 weeks post-operation, followed by 6 monthly PSA levels for 10 years, and yearly PSA levels thereafter. DRE should be performed at every visit. Bone scans, CT scans and prostate bed biopsy are considered in the evaluation for salvage therapy. In absence of raised PSA, yield from imaging is negligible and not recommended (B/III).

6.3 Radiotherapy

Experience in the last 3 decades has demonstrated that radiotherapy is effective in permanent control of prostatic tumours (B/IIa). However, as few patients undergo repeat biopsy of the gland to confirm response, the true incidence of local control may be lower than the 65% to 88% reported. (71 - 76)

• Long-term results of radiotherapy in stage T1 and T2 patients are similar to those reported with radical prostatectomy despite differences in case selection and the lack of surgical staging of the lymph nodes in most cases. The definition of endpoints needs to be considered in non-randomised comparisons. (77)
• The late complications of radiotherapy include chronic mild to moderate cystitis (12.5%), diarrhoea (9.7%), proctitis (7.8%), rectal bleeding (4.4%), urethral stricture or bladder neck contracture (3%) and haematuria (3%). Severe complications are rare. (A/Ib) (78, 79)
• Pelvic nodal irradiation does not confer any benefit in terms of local control or survival (A/Ib). Pelvic nodal involvement is invariably associated with the development of distant metastases. (80, 81)
• The data from the trials (Annex 2) suggest a role for the use of concurrent hormonal therapy with radiation for the treatment of localized prostate cancer. However, the type of androgen deprivation and its duration remains to be established. (B/III) (82 - 84) Complications with radiotherapy for patients treated with neoadjuvant therapy may be lower.
  
  Early reports have shown that 3-Dimensional Conformal Radiotherapy (3D-CRT) may improve local control and survival in patients with prostate cancer. (III/C) (85, 86) Post high-dose radiotherapy morbidity may also be limited by this approach.
• Interstitial brachytherapy is generally not recommended for locally advanced disease: PSA > 10 ng/dl and high Gleason score. (B/IIa) (87 - 90) The morbidity includes substantial bladder toxicity such as dysuria, hematuria and other severe urinary symptoms were reported in this study. 46% of patients required medication to alleviate symptoms. Patients with significant pretreatment lower urinary symptoms are especially at risk, 14% exhibited persistent severe urinary symptoms at 2 years after implantation. 5 patients, early in the series, developed rectal ulcers. This effect was nearly completely eliminated with improved treatment plans. Of the 56 men who were sexually potent prior to implantation, 86% retained potency at 3 years. (A/Ib) (88 - 90)
• To assess for post-treatment disease status, PSA levels done 6 monthly for a period of 10 years and annually thereafter is recommended. (A/Ib) (76) (88, 89) (91) Nadir PSA levels ( < 0.5 ng/ml), typically achieved at 12 to 24 months, is of prognostic significance for relapse.

6.4 Management of Locally Advanced Prostate Cancer
(Stage T3 N0, T4 N0, T1-4 N1)

In accordance to the TNM staging system, locally advanced disease would include T3:N0, T4:N0, and T1-4:N1. There is evidence that long-term survival is possible with control of locally advanced disease confined to the pelvis. (92, 93) Endorectal coils for MRI may enhance imaging of the prostate. (B/III) (94)

Androgen deprivation improves survival of patients with locally advanced prostate cancer. Neoadjuvant hormonal therapy reduces the radiation field size and hence treatment-related morbidity. (B/III) (82, 83) The role of adjuvant hormonal therapy for locally advanced prostate cancer is currently being evaluated. Preliminary findings showed no survival advantage but significant disease-free interval for patients with immediate orchiectomy. (95)

For asymptomatic patients, surveillance is an option. Biochemical failure after definitive local therapy is also included in this section.

Treatment for locally advanced (T3) prostate cancer
While the mainstay of treatment is systemic androgen deprivation therapy, local therapy in the form of radical prostatectomy with adjuvant radiotherapy; hormonal treatment; or radiotherapy with hormonal adjuvant therapy may offer some benefit. (B/III) (96, 97) Neoadjuvant hormonal therapy before radical prostatectomy is not recommended as there is no obvious benefits. (Ib/A) (98)

Treatment for locally advanced (N+) prostate cancer
Radiotherapy with hormonal therapy has been shown to achieve long-term survival but the extent of contribution from the local therapy remains unclear. (99) Radical prostatectomy with adjuvant hormonal therapy is advocated by some who reported good long-term survival. (B/III) (70) (100 - 102)

6.5 Biochemical failure

Biochemical failure is defined as serum PSA levels following surgery at 0.4ng/dl; that following radiotherapy at 0.5 ng/dl; and/or 2 consecutive rising PSA value 3 months apart. (B/II) It is an elevation or consistently raised PSA levels after definitive treatment indicating persistent local or systemic disease. It usually precedes clinical recurrence by up to 3 years.49, (103, 104)

Early elevated PSA levels in less than 12 months post treatment may indicate distant spread of disease. The PSA level in this instance is also significantly higher than that in local recurrence. A short PSA doubling time or PSA velocity of more than 0.75ng/mi/year may indicate systemic recurrence. (B/ III) (105, 106) Elevated PSA levels more than 12 months post treatment may indicate local recurrence.

Patients with biochemical failure need to be investigated for local or systemic recurrences.

• DRE is an unreliable early indicator of recurrence of local cancer following treatment. (B/III) (107)
• TRUS, when used independently, was of no value in the diagnosis of local disease after treatment. However, TRUS has a definite role to facilitate localization and guiding systematic biopsy for patients with elevated PSA and/or suspicious DRE. (B/III) (108 - 111)
• Bone scan may be indicated to detect systemic bony metastasis although elevated PSA levels may precede positive bone scans by a median of 10 months. (107) (112)
• CT/MRI of the abdomen and pelvis may be indicated in evaluating post-prostatectomy patients for adjuvant radiation with elevated PSA levels, normal bone scan, normal TRUS and biopsy. (B/III) (113)
• ProstaScint scan may enhance identification of systemic recurrence after treatment.(GPP) (114)

The presence of disease in non-pelvic lymph nodes, bone or distant (other than pelvis) sites constitutes the definition of M1/D2 disease. The presence of visceral or lytic metastatic lesions should alert clinicians of variant histology (e.g. neuroendocrine tumour) (A/Ia).

7.1 First line treatment

Hormonal therapy achieved favourable response in 75 - 80% of patients with advanced prostate cancer, although the median duration of response is 18 months and the median survival time is 36 months. Early treatment improves local and distant disease control. (Ib/B) The different treatment modality orchiectomy, luteinizing hormone-releasing hormone (LHRH) analogue and diethylstilbesterol (DES), though differing in toxicity and costs, give equivalent results. (115 - 118)

• Medical Research Council Trial (MRCT), United Kingdom, reported significant delay in disease progression with no survival difference in cases with stage M0 prostate cancer under hormonal therapy. A randomized study from National Cancer Institute (NCI) reported that early androgen deprivation improves local and distant disease control with no survival benefits. A French study reported significant overall and disease-free survival favouring early LHRH treatment. Another large MRC randomized study on early vs deferred hormonal therapy reported improvement in local and distant disease control in stage M0 & M1 cases of prostate cancer with survival benefits only seen in the stage M0 group. (80) (95) (119) (120)
• However, early treatment exposes patients to longer duration of hormone-associated toxicity including osteoporosis, hot flushes, sexual dysfunction (decrease libido), gynaecomastia, nausea, vomiting, diarrhoea, insomnia and lethargy. (121)
• Total androgen blockage (TAB) is not recommended presently. (A/Ia) Previous advocates of TAB, US NCI intergroup 0036, the European Organization for Research and Treatment of Cancer (EORTC) phase III study and a Dutch study reporting significant progression-free survival benefits have been refuted by recent studies and a large meta-analysis of 22 studies. (122 - 127)

TAB may be indicated under some special circumstances:

• Flare prevention during first month of LHRH agonist therapy
• Severe symptoms as faster relief associated with initial TAB
• As second-line therapy (B/IIb) (128, 129)

• Intermittent androgen suppression is currently experimental, (III/C) although there are certain encouraging animal and phase II study results. It is associated with lower costs and improved quality of life (sense of well being, recovery of libido and potency). Currently, phase III trials are ongoing. (130 - 133)
• Monotherapy with bicalutamide or finasteride are at present not recommended. (A/Ib)

7.2 Second-line treatment

In Singapore, 50% of prostate cancer present as stage D2(M1) while only 24% of prostate cancer in USA present as such. Between 1989 and mid 90s, the first-line treatment was castration (orchiectomy (134) or drug therapy with estrogen or LHRH agonist), antiandrogen or combined androgen blockade, (CAB - a combination of castration and antiandrogen). However, recent data suggests that CAB does not offer a significant survival advantage over castration alone (monotherapy). First-line treatment, whether monotherapy or CAB, usually controls disease for only 12-18 months and second-line treatment is very often necessary. (A/Ib) (122) (123) (125) (135)

Definition of 'second-line therapy' of prostate cancer

• Progression
  * Increase in size of measurable lesions, or the appearance of new measurable lesions; or
  * Increase in PSA levels of at least 50% on at least 2 consecutive measurements, at least 2 weeks apart; or
  * Increase in pain associated with new bony (non-measurable) lesions; or
  * Combination of above.
  
• Adequate primary hormonal treatment
  Defined by castration level of testosterone.

Overview of second-line treatment of prostate cancer
Second-line treatment of prostate cancer has not shown consistent survival advantage. Median survival is still less than 1 year following relapse. Palliation of symptoms is an important endpoint. The selection of further treatment following relapse depends on many factors, including prior treatment, site of recurrence, coexistent illnesses, and individual patient considerations. The absolute level of PSA at the initiation of therapy in hormone-refractory patients has not been shown to be of prognostic significance. Data on PSA changes while on chemotherapy being predictive of survival are conflicting. (136, 137)

Problems associated with second-line treatment trials include

• Treatment endpoints in many earlier trials are not well defined: e.g. stable disease (SD) has been regarded as evidence of response in some trials but not in others. 89% of so-called responses have been SD's. Most feel that SD is not a valid indicator of response in prostate cancer.
• Fall in PSA levels is potentially confounding: (138, 139)
  i. PSA decline correlates with measurable response in only 68% of the time.
  ii. PSA decline may be due to a fall in rate of PSA gene expression, rather than loss of prostate cancer cells.
• Patients with no measurable disease are often excluded from trials, but patients with measurable disease (e.g. soft tissue lesions) may not be representative of prostate cancer as a group. 80-90% of prostate cancer patients do not have measurable diseases.
• Documentation of the cause of deaths in elderly prostate cancer patients is not always reliable, given the presence of comorbidity.

What is the preferred second-line treatment?

• For patients who are using only LHRH agonist or oestrogen as primary therapy, but whose testosterone level is not below castration level, adding an antiandrogen is useful. (GPP)
• Patients who are using only LHRH agonist or oestrogen as primary therapy, but whose testosterone level is at castration level, defined as the limit of detection in individual laboratories, may benefit from indefinite use of LHRH agonist. (B/III)
• For patients who are using antiandrogens or CAB, antiandrogen withdrawal is the preferred approach. (B/IIa) It may be useful to continue prescribing LHRH agonist indefinitely once it has been started even in relapse cases. However, data on this issue is conflicting. (140, 141)
• Antiandrogen withdrawal is mostly applied to flutamide and bicalutamide and is the preferred approach at relapse. (142) Although their responses rates are similar, flutamide discontinuation leads to a much quicker appearance of response (days versus weeks). 20% response rate can be expected from antiandrogen withdrawal lasting a median of 3.5 to 5 months (anecdotal cases of up to 2 years).(142, 143) A prolonged period of flutamide usage is more likely to produce favourable withdrawal response.
• Withdrawal benefits of megestrol acetate, a progesterone agent which acts centrally as well as at the androgen receptor, has also been reported. (B/IIb) (144)

Other treatment options
Beyond the measures described in the previous section, the following options have been used although there is insufficient data to guide the choice among them. (III/C)

Addition of a second antiandrogen
Changing to bicalutamide after failure of flutamide therapy has been shown to produce a 20% response rate and the effect is dose-dependent - 150-200 mg daily being preferred to 50 mg. However, flutamide for bicalutamide failure has not been evaluated. (145)

Adrenal androgen inhibitors
i. Aminoglutethimide (250 mg po tid) + replacement hydrocortisone
A review of 13 randomised trials showed 9% objective response rate. The adverse effects include fatigue, rashes, orthostatic hypotension, and ataxia. (144)
ii. Aminoglutethimide + replacement hydrocortisone + flutamide withdrawal
This has been shown to produce responses in heavily-pretreated patients.(146) Ketoconazole can produce a 15% objective response and 78% PSA response at 400 mg po tid + replacement hydrocortisone. Ketoconazole 200 mg tid has been documented to produce similar results with no replacement hydrocortisone. The medication is taken with an empty stomach as low pH promotes absorption. (143, 147)

Supportive care with prednisolone
Low-dose glucocorticoids (e.g., prednisolone 10 mg daily) is effective and achieve reasonable palliative relief for patients who are not fit for aggressive chemotherapy. (A/Ib) (148) Low-dose prednisolone is probably as effective as the addition of flutamide as a second-line therapy. (B/IIa) (149)

Chemotherapy or chemohormonal therapy
Before 1991, the response rate of chemotherapy ranges from 4.5 to 8.7%. (150, 151) New drugs and drug combinations with more potent antiemetics and the use of PSA levels as a monitoring tool, have led to a renewed interest in chemotherapy in the 1990s. Many new clinical trials are currently underway.

i. Mitoxantrone + prednisolone (M+P)

M+P combination is USFDA (United States, Food and Drug Administration) approved and produced a 29% response rate with palliation of pain as the endpoint as well as a longer duration of palliation in a Canadian randomised trial. The result was better than prednisolone alone (12% response rate with similar endpoint). The survival benefit was possibly due to cross-over design. (B/Ib) (148)

ii. Estramustine + estramustine-based combinations
Estramustine binds to microtubule-associated proteins.

• Oral estramustine alone produced 19% objective response rate in 18 phase II trials.
• Estramustine (10-15 mg/kg po daily) + vinblastine (3-4 mg/m2 IV weekly) produced 40% objective response rate and 54% PSA response in phase II studies. Estramustine + vinblastine combination was superior to vinblastine alone in aphase III study. (B/IIb) (125) (152 - 155)
• Estramustine (15 mg/kg po daily) + etoposide (50 mg/m2 po daily) for 21 days out of 28 days is an active combination. (156)
• Estramustine + paclitaxel (120 mg/m2 over 96 hours) combination every 21 days. Two drugs that impair microtubule function by complementary mechanisms. (154)

iii. Other chemotherapeutic agents

Doxorubicin (20 mg/m2 IV weekly) produced 16% objective response. Doxorubicin (20 mg/m2 weekly) + ketoconazole (400 mg po tid) for 6 weeks, rest 2 weeks, produced 58% objective response and 55% PSA response. Doxorubicin + ketoconazole alternating with estramustine + vinblastine produced a 75% objective response that lasted 8.4 months, with an overall survival of 19 months. Estramustine + weekly doxorubicin produced 45% objective response, 58% PSA response and 27% subjective response. Estramustine + etoposide + cisplatin (or carboplatin) produced an objective response of 61%. (157 - 160)

Suramin in hormone refractory prostate cancer
Suramine inhibits PDGF, TGF-beta and other growth factors. In phase II studies, it produced 20% PSA responses. However, negative studies have also been reported. Toxicities included polyradiculopathy, myelopathy, coagulopathy and vortex keratopathy. Phase III multicentre study reported significant palliative advantage and delay disease progression. (136) (161 - 165)

Radiotherapy

• External beam irradiation is indicated for painful bony metastases, or unstable bony metastases.
• Hemibody irradiation is indicated for patients who have too many symptomatic bony metastases to be treated individually
• Radioisotopes such as Strontium-89 and Samarium-153 are beta-emitting isotopes which can improve bone pain in up to 70% of the treated patients. However, this may cause myelosuppression, especially if chemotherapy is subsequently needed. (166)

Bisphosphonates can reduce bone pain in up to 76% of the treated patients. (B/IIb) (167)

Assessing treatment responses

Given the different treatment endpoints in prostate cancer, it is necessary to report and analyse treatment data based on individual endpoints.
Accepted treatment endpoints in prostate cancer are:

i. Objective response of measurable disease;
ii. PSA response; and
iii. Subjective response

It is known that PSA decline of >50% confers a better survival advantage compared to < 50% PSA decline. (168)
One of the most robust treatment endpoint in prostate cancer is survival. In this regard, the overall survival is probably more reliable than disease-specific survival since documentation of the cause of deaths in prostate cancer is often not reliable.

There is an urgent need for good research on early detection methods focussed on Asians to direct future programs in disease control. Randomised control trials to compare radiotherapy with observation should be carried out. Improvement in techniques to minimize morbidity and improve curative rate should be explored. Most of the data quoted are from Western literature, there is a paucity of well-designed Asian studies. As the epidemiology of prostate cancer is very geographically dependent, studies focussing on the differences may eventually shed light on the etiology and natural history of this disease.

i. Differentiation agent
ii. Cdk inhibitor
iii. Pro-apoptotic agents
iv. Antiangiogenic agents
v. Genetic immunotherapy

I/C: Dr Christopher Cheng (Chairman)

Members:
1. Dr Yang Tuck Loong
2. Dr Chia Sing Joo
3. Dr Ng Foo Cheong
4. Dr Damian Png
5. Dr Toh Khai Lee
6. Dr Christopher Chee
7. Dr Sidney Yip
8. Dr Karmen Wong
9. Dr Kong Hwai Loong
10. Dr Lewis Liew
11. Dr Ng Lay Guat
12. Dr Terence Tan
13. Dr Tan Yeh Hong
14. Dr Robert Lim
15. Dr Tan Puay Hoon

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(Union Internationale Contre le Cancer - American Joint Committee on Cancer - UICC-AJCC)

Primary tumor (T)
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
T1 Clinically inapparent tumor not palpable or visible by imaging
T1a Tumor incidental histologic finding in 5% or less of tissue resected of Gleason score not more than 5
T1b Tumor incidental histologic finding in more than 5% of tissue resected or of Gleason score more than 5
T1c Tumor identified by needle biopsy (e.g., because of elevated PSA)
T2 Tumor confined within prostate*
T2a Tumor involves half of a lobe or less
T2b Tumor involves more than half of a lobe but not both lobes
T2c Tumour involves both lobes
T3 Tumor extends through the prostatic capsule**
T3a Unilateral extracapsular extension
T3b Bilateral extracapsular extension
T3c Tumor invades seminal vesicle(s)
T4 Tumor is fixed or invades adjacent structures other than seminal vesicles: bladder neck, external sphincter, rectum, levator muscles, and/or pelvic wall
*Note: Tumor found in 1 or both lobes by needle biopsy, but not palpable or reliably visible by imaging, is classified as T1c.
**Note: Invasion into the prostatic apex or into (but not beyond) the prostatic capsule is not classified as T3, but as T2.

Regional lymph nodes (N)
Regional lymph nodes are the nodes of the true pelvis, which essentially are the pelvic nodes below the bifurcation of the common iliac arteries. They include the following groups (laterality does not affect the N classification): pelvic (NOS), hypogastric, obturator, iliac (internal, external, NOS), periprostatic, and sacral (lateral, presacral, promontory (Gerota's), or NOS). Distant lymph nodes are outside the confines of the true pelvis and their involvement constitutes distant metastasis. They can be imaged using ultrasound, computed tomography, magnetic resonance imaging, or lymphangiography, and include: aortic (para-aortic, periaortic, lumbar), common iliac, inguinal, superficial inguinal (femoral), supraclavicular, cervical, scalene, and retroperitoneal (NOS) nodes.

NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in regional lymph node or nodes
Abbreviation: NOS, not otherwise specified.

Distant metastasis*** (M)
MX Distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis
M1a Nonregional lymph node(s)
M1b Bone(s)
M1c Other site(s)
***Note: When more than 1 site of metastasis is present, the most advanced category (pM1c) is used.

Histopathologic grade (G)
The Gleason classification scheme is currently the most commonly used system. Low power magnification is used to assess the glandular pattern of the rumour and the relationship to the stromal compartment. Five tumour grades progressing from the most (1) to the least (5) differentiated are recognised. The final grade assigned the tumour is a sum of the grade of the five tumour patterns that constitute the largest and nest largest tumour mass.

Gleason 2-4 well differentiated
Gleason 5-7 moderately differentiated
Gleason 8-10 poorly differentiated

Results of Conventional External Beam Radiotherapy in Stage T1 to T3 Carcinoma of the Prostate (from De Vita 5th Edition)