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CURRENT MANAGEMENT OF PROSTATE CANCER

B D Kashyapi*, Ramesh Gulla**, J N Kulkarni***
*Research Fellow; **Clinical Fellow, Consultancy Urooncologist, Bombay Hospital Institute of Medical Science; ***Professor and Head, Division of Uro Oncology, Tata Memorial Hospital, Mumbai 400 012.

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INTRODUCTION

Prostate cancer incidence is increasing in India. The outlook for prostate cancer has considerably changed in the last decade. Cancer prostate was earlier believed to be an indolent tumour and, invariably, hormonal manipulation in some form was the therapy offered. Increasing patient and physician awareness had led to diagnosis of more early stage cancers. In order to offer appropriate therapy to an individual patient, it is necessary to keep abreast of the recent developments in the field.

Epidemiology

Prostate cancer ranks 2nd in cancer related mortality for men in USA. Though uncommon in Asian countries, the incidence is increasing even in our country. Currently, it ranks 5th in incidence and 4th in cancer mortality for men in Mumbai. [1] The incidence is increasing by 1% every year. It is more common in the Parsi community in Mumbai.

Aetiology

Several factors are believed to be causally associated with increased risk for prostate cancer. It is highest in countries like Sweden, USA, and Europe while it is lowest in Taiwan and Japan. Environmental and geographical factors play role in some geographical areas. High consumption of dietary fats (fatty acids, alpha lenoic acid in red meat/butter), deficiency of trace element like selenium and low levels of Vit D3 and Vit E have been implicated in increased risk of developing of prostate cancer. About 10-15% of patients have positive family history and the risk is increased in these individuals. Definite recommendations can be made for screening men at increase risk.

Pathology

Almost all of prostate cancers are adenocarcinomas, the other histologic types being rarely seen. Histological grade is the most information obtained from the biopsy. Widely accepted Gleason’s scheme assigns histologic grades of 1 to 5 depending upon the architectural pattern of acini. Gleasons score is the sum of two most predominant grades. Prostate cancer arises commonly in the peripheral zone and is multifocal in nature. This makes it impossible to completely remove it with transurethral resection.

Natural History

Histological grade (Gleason’s scheme) is the most important factor affecting the natural history. Tumour with a Gleason score of 2 to 4 is compatible with life while that with a score of 5-6 carried a slightly higher but significant risk of death from prostate cancer. Tumour of score 7-10 is fatal even in advanced age of more than 70 years. [2] Low grade tumours remain localized for a long time while high grade tumours spread along nerve sheaths, along lymphatic chains and by haematogenous route. Distant metastases are commonly present when lymph nodes are involved.

Symptomatology

In men over 50 years with complaints of dysuria, frequency and voiding difficulty, a high index of suspicion is necessary before attributingthese symptoms to benign prostatic hyperplasia. Symptoms in the early stage are indistinguishable from that due to BPH. Digital rectal examination and measurement of serum PSA help in avoiding diagnostic pitfalls. Presence of dysuria, voiding difficulties, haematuria and urinary retention usually point towards locally advanced disease. Lymphatic obstruction due to nodal metastases gives rise to scrotal, penile or pedal oedema. Pain in back, pelvis, legs, shoulders or over multiple bony sites is due to development of bony and vertebral metastases. This, unfortunately, is still one of the commonest presentations of prostate cancer in our country. Many patients are also diagnosed after performance of TUR with a presumed diagnosis of BPH "histological surprise".

High index of suspicion, physical examination and use of serum PSA (and prostatic biopsy if indicated) before initiating any patient on medical therapies (prazosin, terazosin or finasteride) shall help in diagnosing cases at earlier stage when appropriate and effective therapies can be offered.

Physical Examination y

Digital rectal examination reveals hard/firm nodule(s), loss of normal rubbery consistency of gland, periprostatic spread or uniformly hard gland. If you don’t put your finger in the rectum, you put your foot in it. [3] In advanced cases, palpable bladder, enlarged iliac or supraclavicular nodes and sites of bony tenderness may be detected.

Laboratory Studies

These include CBC, urinalysis, renal and liver function tests, alkaline phosphatase and chest X-ray. Raised alkaline phosphatase may be due to liver or bony metastases.

Serum PSA

PSA availability in the last decade has had a great impact on the overall diagnosis, treatment and follow up of prostate cancer. It is a serine protease whose physiological role is in liquefaction of the semen coagulum. The normal range is 0-4g/ml. Level more than 10 ng/ml is a definite indication for prostatic biopsy. Intermediate range PSA (4-10) can be resolved by refined tests like PSA density, PSA velocity and transitional zone PSA. Age reference PSA and % free PSA are helpful in screening for prostate cancer. These refinements help in avoiding unnecessary negative biopsies without missing important cancers. PSA is highly sensitive and helps in the detection of primary, residual and recurrent cancer of very low volume. Elevated levels may also be seen with prostatitis, cystoscopy, prostatic biopsy but not after digital rectal examination. About 10% of proven prostate cancer patients have normal PSA levels.

Acid phosphatase

It is inaccurate and not sensitive enough, hence its utility is nonexistent these days.

Imaging Studies

TRUS (Transrectal ultrasound), CT scan, MRI pelvis, bone scan and skeletal survey are carried out depending upon symptoms, clinical findings and clinical staging. For organ confined prostate cancer, TRUS and MRI can detect capsular breach. TRUS is useful for guided biopsies. Bone scan is indicated in patients with PSA > 20 ng/ml.

Histological Diagnosis

Trucut prostatic needle biopsy with determination of histological grade is essential. Examination of prostatic chips after TUR is also one of the common modes of diagnosis.

Staging System

Currently, TNM system of classification is uniformly used rather than Whitmore-Jewett’s ABCD staging system. Management

Prostate cancer treatment was synonymous with hormonal manipulation in our country in the past. This scene is fast changing with better awareness about current modalities of treatment. Age of the patient, co-morbid conditions, histological grade and stage of the disease are the factors taken into consideration when deciding treatment for a particular patient.

Clinical staging is inaccurate in significant number of patients and pathological upstaging frequently results. Tumour grade is an important prognostic factor. Patients with Gleason score 2-4 tumours have only 5% chance of dying from prostate cancer over 15 years of observation. Those with a score of 5-6 have 6-30% risk and those with 7-10 score have a high risk 42.87%.

Early S tage (T1/T2NOMO)

Options available are

1. Radical prostatectomy
2. Radical radiotherapy
3. Watchful waiting

Radical Prostatectomy

It includes ilio-obturator node dissection, retropubic excision of prostate and seminal vesicles followed by vesicourethral anastomosis. It can be done by either the standard retropubic or by the perineal route. Principal complications are urinary incontinence (total upto 4%, stress incontinence upto 30%) and erectile impotence. Nerve sparing modification can preserve erections in many patients desiring to maintain erection (Walsh’s modification).

Since 1992, we have performed more than 75 radical prostatectomies at Tata Memorial Hospital for early stage cancer. At a median follow up of 30 months, only 1 patient has died from prostate cancer. Overall the results appear encouraging with 5 local and 10 distant relapses.

Radical Radiotherapy

Radical RT is indicated in a patient if his medical co-morbid conditions precludes surgery and when gross nodal disease is found during surgery. It is also administered in adjuvant setting for positive surgical margins after prostatectomy.

External RT consists of 7000 cGy given over a period of 7-8 weeks. Brachytherapy (Iodine 131 seed implants, Ir192 perineal template) and 3-D conformal radiotherapy give better results with less complications. Common complications are acute toxicities like frequency and dysuria, suprapubic and penoscrotal oedema (20%), erectile impotence (50-60%), radiation proctitis and radiation cystitis (5%). Experience with brachytherapy techniques is limited at our hospital.

10-15 year survival rates favour surgery over RT. In high grade tumours, 10 year survival rates (cancer specific) are 67% for radical prostatectomy as compared to 535 for radiotherapy and 45% for watchful waiting. [4]

Watchful waiting

Elderly patients with comorbid medical conditions, limited life expectancy and low grade tumours (Gleason score 2-4) can be observed with watchful waiting. Intervention in the form of TUR for obstructive voiding symptoms or hormonal manipulations may be required in some patients.

Locally Advanced Stage (T3 NOMO)

1. Radical prostatectomy
2. Radical Radiotherapy
3. Hormonal Therapy

Radical prostatectomy understages clinical T3 disease to T2 in about 10% of patients. [5] Accurate staging of lymph nodal status is also provided. Local complications like obstructive urinary complaints and haematuria are significantly less as compared with those given either radical RT or only hormonal therapy. Prostatectomy is also believed to remove a potential nidus for development of metastatic disease. Radiation therapy may be preferred in patients who are sexually active. Short term neo adjuvant hormonal ablation is shown to improve the results of radiotherapy. [6] Hormonal therapy (bilateral orchiectomy or sometimes LHRH analogues) can be given to elderly, infirm patients who decline any further therapy. Even patients diagnosed incidentally (asymptomatic), watchful waiting is not advocated as proved by a recent MRC trial. [7] Early castration significantly decreases complications like fractures, cord compression, ureteric obstruction and non osseous metastases.

Metastatic Disease

Early endocrine therapy is the mainstay of treatment in the management. Hormonal dependancy of prostate cancer was the Nobel prize winning discovery made in 1941 by Higgins and Hodges. Since then bilateral orchiectomy (total/subcapsular) is the gold standard of hormonal therapy. Improvement of symptoms, especially bony pain due to metastases, is often dramatic. Immobilized, bedridden patientare able to become more functional and ambulant. For those unwilling for orchiectomy, other means of hormonal deprivation are available. Diethyl stilbesterol (DES) 1 to 3 mg PO brings serum testosterone to near castrate levels. But the incidence of cardiovascular and thromboembolic complications is very high. Gynaecomastia (sometimes painful) develops in some patients. Honvon (fosfesterol sodium) is a bone seeking synthetic analogue which in the dosage of 50-200 mg even TID is equivalent to DES. Luteinising hormone releasing hormone analogues (LHRH analogues) like leuprolide 7.5 mg or goserlin 3.6 mg (Zoladex) (depot preparations, monthly/trimonthly, administered deep subcutaneously) are the medical means of achieving castrate levels of testosterone. These are supplemented with antiandrogens like flutamide for the initial period of 10 days to counter the initial testosterone surge. But the disadvantage of these injections is their prohibitive cost (a single injection of Zoladex costs About Rs. 7,000-8,000). The concept of total androgen blockade was introduced in 1983 by Labrie and coworkers. It was proposed to block even the adrenal source of androgens. Many initial studies were conducted which supported its role. However recently concluded large randomised controlled trial comparing orchiectomy versus orchiectomy and flutamide failed to show any survival advantage to the combination group. [8]

The Urological Society of India has recently initiated a study to evaluate the efficacy of total androgen blockade in our patients. Patients with metastatic prostate cancer shall be entered into this study to evaluate the efficacy of orchiectomy versus orchiectomy and flutamide.

Other agents like medroxyprogesterone acetate and cyproterone acetate are infrequently used. Aminoglutethimide and ketoconazole (Androgen synthesis inhibitors) are usually reserved as second line agents.

HORMONE REFRACTORY PROSTATE CANCER (HRPC)

Most of the patients with metastatic prostate cancer become hormone unresponsive (due to growth of hormone insensitive and hormone independent cell lines) at a median period of 18-24 months. In such patients management is often difficult and palliation of symptoms remains the primary goal. Withdrawal of antiandrogens (if these drugs are in use at that time) is the first step (flutamide withdrawal syndrome). Patients with good performance status can be tried with cytotoxic chemotherapy. Estramustine hydrochloride has shown response rates of 20% but addition of other agents has not improved the results. Mitoxantrone (12 mg IV every 3 weekly) has also shown significant palliative benefit recently. [9] Differentiating agents like liarozole have been shown to slow disease progression and are likely to be used frequently in future. [10]

Palliation of Bony Metastases

External beam radiotherapy (EBRT) is effective for isolated painful bony metastases. Hemibody irradiation (6 Gyfor upper half and 8 Gy for lower half) is helpful in extensive skeletal metastases. Bone seeking radio-pharmaceuticals such as phosphorus 32 and strontium 89 are equally effective. Analgesic requirements are reduced. P-32 is cheaper and is supplied by BARC, India while St-89 is imported and expensive. Fresh appearance of painful sites is less frequent with radio-pharmaceuticals than with hemibody irradiation. [11] Combined radiation and radio-pharmaceuticals has been found to be more effective than individual combinations. Osteoclast inhibiting agents- biphosphonates (etidrate, pamidronat, clodronate) have also given pain relief lasting up to 3 months after a single IV dose. Prednisolone also gives relief in some patients.

Appropriate use of analgesics (non-narcotic and narcotics) in adequate doses is also very important in giving pain relief. It is important to give laxatives along with narcotic analgesics. Unlike the common belief oral/iv morphine is not addictive can be easily given under medical guidance for total pain relief. Many oral morphine preparations are readily available in the market.

Other Clinical Problems

Fig. :

Paraparesis/Paraplegia

Impending paraparesis is a surgical emergency. Early ablation therapy (orchectomy, LHRH analogue + antiandrogen or ketoconazole) is essential. Decompression may be considered when imaging studies show localized areas of compression on the spinal cord. Once paraplegia is established, the prospects of recovery are dismal.

Haematuria

Haematuria due to locally advanced prostate cancer is seen occasionaly. Conservative management like catheter drainage, irrigations and rarely fulguration of specific bleeding points also suffice in addition to hormonal manipulations.

Refractory anaemia and obstructive uropathy are the usual end stage problems. Uraemic death is often a means of relatively peaceful death and aggressive interventions is generally not advocated.

Prevention and Early detection

Prevention

Dietary modifications early in life may help in prevention. One randomized study has shown that trace element selenium supplementation decreases the incidence of prostate cancer significantly. [12] Role of finasteride (5 alpha reductase inhibitor) in preventing prostate cancer is keenly awaited.

Early detection

Value of digital rectal examination and PSA test in early detection has been confirmed. Recommended below is an algorithm based on DRE and PSA testing for early detection of prostate cancer.

CONCLUSION

Prostate cancer incidence is rising in our country. Though early cases are being detected, still the majority are diagnosed in metast Öastic stage. There is a need to increase the awareness amongst physicians as well as patients for the need for early detection and treatment of this disease. Early detection and effective ablative treatment like radical prostatectomy can decrease prostate cancer deaths. [13] Significant improvement in palliative care has also been achieved for advanced stage patients.

REFERENCES

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3. Footnote in Bailey and Love’s Textbook of Surgery, 21st edition. 1992; 1199.
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6. Bolla M, Gonzalez D, Warde P, et al. Improved survival in locally advanced prostate cancer treated with radiotherapy and goserlin. N Eng J Med 1997; 337 : 295.
7. The Medical Research Council Prostate Cancer Working Party Investigation Group : Immediate versus deferred treatment for advanced prostate cancer, Initial results of Medical Research Council trial. Br J Urol 1997; 79 : 235.
8. Eisenberger MA, Blumenstein BA, Crawford ED, et al. Bilateral orchiectomy with or without flutamide for metastatic prostate cancer. N Eng J Med 1998; 339 : 1036.
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10. Debruyne FJ, Murray R, Fradet Y, et al. Liarozole-a novel treatment approach for advanced prostate cancer : Results of a large randomized trial versus cyproterone acetate. Liarozole Study Group. Urology 1998; 52 : 72.
11. Quilty PM, Krikk D, Bolger JJ, et al. A comparison of palliative effects of strontium-89 and external beam radiotherapy in metastatic prostate cancer. Radioth Oncol 1994; 31 : 33.
12. Clark LC, Dalkin B, Krongard A, et al. Decreased incidence of prostate cancer with selenium supplementation : results of a cancer prevention trial. Br J Urol 1998; 81 : 730.æ
13. Mettlin CJ, Murphy GP. Why is the prostate cancer death rate declining in the United States? Cancer 1998; 82 : 249.

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