Incidence and etiology. Prostate cancer is the second most common malignancy in male adults as well as the second most common cause of cancer-related deaths in the United States. The American Cancer Society estimates that prostate cancer was newly diagnosed in 317,000 patients in 1996, and 41,000 deaths resulted. In 1998, the incidence of new patients decreased to just above 200.000 with an estimated 40,000 deaths. The chance of a man acquiring prostate cancer during his lifetime is about 15%. The incidence of prostate cancer is 50% greater in blacks than in whites and relatively uncommon in Asians. The cause of prostate cancer is unknown, but several associations have been noted.
- Genetic Influences The risk for development of prostate cancer is increased two to three lines if a father or brother has had the disease.
- Hormonal Factors Virtually all prostate cancer cells exhibit some degree of androgen dependence. This is supported by the observation that prostate cancer does not occur in eunuchs.
Chemical factors Workers in the rubber, fertilizer, and textile industries have increased rates of prostate cancer, as do men continuously exposed to cadmium, a known antogonist of zinc. A diet high in saturated fat and cigarette smoking have also have been suggested to have an association with prostatecancer.
Other factors In comparison with controls, patients with prostate cancer have been noted to be more sexually active, more promiscuous, and more likelyl to have been exposed to venereal disease, although no cause and effect relationships have been demostrated.
Tumor histology and grading More than 95% of prostatic neoplasms are adenocarcinomas arising from prostatic acinar cells at the periphery of the gland. This contrasts with benign prostatic hyperplaisa (BPH) which develops from inner periurethral tissues. Squamous cell carcinoma and transitional cell carcinoma of the prostate occur only rarely. Prostate cancer exhibits a wide variety of histologic appearences, even within the same specimen. There is no universally accepted system of grading the degree of malignancey: however, all systems take into account in varying degree the cytologic characteristics and the glandular morphologic characteristics.
- The Mostofi System taken these two factors into account equally in a three-grade system.
- The M.D. Anderson Hospital System ignores cytologic findings and assesses the percentage of gland formation in a four grade system.
The Gleason System Also ignoring cytologic features, Gleason established five grades of glandular morphology. The two most prominent glandular patterns are graded from 1 to 5. The sum of these two grades will range from 2 to 10, with 2 representing the most differentiated and 10 representiing the most anaplastic tumors. There is a rough correlation between the Gleason grade and the biologic behaviour of the tumor, but this is also true of other grading systems. The Gleason system is the one most widely used today because it has the best clinical correlation.
- The Mostofi System taken these two factors into account equally in a three-grade system.
Diagonosis and staging Until the advent of measurement of prostate specific antigen (PSA) prostate cancer was usually clinically silent until metastatic disease produced symptoms. Diagnosis depended entirely on routine digital rectal examination. The digital prostate examination is still very important, but at present many other studies also contribute to diagnosis and staging.
Prostate biopsy or aspiration cytology Prostate biopsy is most commonly performed through the transperineal approach with various types of instruments. The transrectal approach may also be used. A discrete area of induration in a man older than 50 has a 50% chance of being carcinomatous on transperineal or transrectal needle biopsy. Transrectal US improves diagnostic senstivity and increases the accuracy of fine-needle aspiration.
Route of Spread Prostate cancer spreads by lymphatic and hematogonous routes. The primary sites of lymphatic metastases are the externalliac (obturator group), internal iliac, and presacral nodes. In general the larger and less differentiated the primary tumor, the higher the incidence of lymphatic metastases. Occassionally, the supraclavicular nodes are involved via the thoracic duct. Hematogeneous spread to bone, lung liver, and kidneys occurs late in the disease.
- Tumour Markers
Prostate-specific antigen (PSA) is a glycoprotein produced only by prostate cells. Thus, it is specific to the prostate but not to prostate cancer. PSA levels have been measured in various ways, including PSA density, PSA velocity, age-specific PSA velocity, age-specific PSA, and free PSA. The advantages of these approaches remain to be established. Nevertheless, PSA measurementsis very useful (a) for screening asymptomatic men (in conjunction with digital rectal examination) b) as an aid in staging prostate cancer, especially with respect to seminal vesicle and lymph node involvement, and © as a way to follow response to radical prostatectomy and radiotherapy.
Prostatic acid phosphatase was the most widely used tumor marker in the past but is rarely used today. It is elevated in 75% to 80% of patients with metastatic prostate cancer and iin 10% to 30% of patients with local disease. It lacks the specificity and sensitivity needed to be a reliable screening test for prostate cancer. It remains occassionally useful in detecting metastatic disease and in monitoring therapy.
Bone Scanning is very useful in detecting metastatic disease. Bony metastases occur in about 80% are osteoblastic: the rest are mixed osteoblastic and osteolytic lesions. Phosphate labeled with technetium 99m is rapidly taken up by bone, which is metabolically active. Bone scans are less specific than radiography, and increased uptake occurs in arthritis, fractures, Paget’s disease, and hyperparathyroidism and after recent trauma. Recent reports have suggested that a bone scan may be omitted if the PSA level is below 10 ng/ml in a patient with prostate cancer.
CT can assess gross local extension and nodal metastases larger than 2 cm. The sensitivity is unhacceptably low, ranging from 27% to 75% Specificity is between 66% to 100%
Transrectal ultrasonography (TRUS) has been shown to be valuable in assessing the presence and extent of prostate cancer. Its role in diagnosis stems primarily from its ability to detect small lesions and guide biopsy procedures. It is very accurate in the assessment of capsular invasion, especially into the seminal vesicles. As an isolated examination, however, TRUS is not a useful staging modality at the current time.
Pelvic Lymphadenectomy remains the most accurate staging method available. The external iliac, obturator, and internal iliac lymphatic chains are dissected bilaterally for pathologic examination. The surgical morbidity is minimal and includes wound complications, lymphocele, and lymphedema of the penis and lower extremities, Pelvic lymphadenectomy is generally performed in conjunction with radical retropublic prostatectomy. It is generally omitted in patients selected for radical perineal prostatectomy, brachytherapy, or external beam radio-therapy. The PSA level may be used to predict. The incidence of pelvic lymph node involvement (Table 4.18)
Molecular staging Polymerase chain reaction amplification can detect circulating PSA messenger ribonucleic acid (mRNA) in the blood or bone marrow of patients with known metastatic disease. However the clinical applicability of this test is not yet known as the percentage of false positive and false-negative results is high.
Other newer techniques Such as endorectal coil MRI and monoclonal antibodies may provide a more precise localizationof prostate cancer. Preliminary studies of monoclonal antibodies report positive predictive values ranging from 50% to 80%.
Staging Nomenclature The AJCC, staging system is gradually replacing the Whitmore-Jewett system that was widely used in the past
Approach to treatment by stage of disease Treatment methods for localized disease include surgical, radiotherapeutic, and hormonal approaches. These are summarizsed in Table 14-10. See chapter 15 for specific information on hormonal and chemotherapeutic agents and Chapter 16 for a discussion of radiation therapy.
|PSA||Pathologic evidence of Capsular penetration %||Pathologic evidence of Seminal vesicle involvement %||Pathologic evidence of Positive lymphnodes %|
|< 0r = 4||25||1||1|
|4.1 – 10||30||5||10|
|10.1 – 20||40||20||20|
|> 0r = 20.1||30||20||35|
|AJCC Stage Primary Tumor||Description||Whitmore-Jewett Stage|
|Tx||Tumor cannot be assessed|
|T0||No evidence of tumor|
|T1a||Tumor found incidentally at TURP(<5% of resected tissue)||A1|
|T1c||Nonpalpable tumor identified because of an elevated PSA value||B0|
|T2a||Tumor involves one lobe||B1|
|T2b||Tumor involves both lobes||B2|
|T3a||Extracapsular Extension(uni or bilateral)||C1|
|T3b||Seminal vesicle involvement||C2|
|T4||Tumor invades the bladder neck,external sphincter, levator muscle, pelvic side wall or Elevated PAP||D0|
|AJCC Stage Lymph nodes||Lymph nodes|
|Nx||Regional nodes not assessed|
|N0||No regional lymph node metastasis|
|N1||Metastasis to regional (Pelvic) lymph nodes|
|AJCC Stage Metastases||Description||Whitmore-Jewett Stage|
|M1a||Metastases to nonregional lymph nodes||D2|
|M1b||Metastases to bone||D2|
|MIc||Metastases to other sites||D2|
|Hormone-refractory Metastatic disease
Prostate cancer Screening Although the impact of prostate cancer screening and early detection programs is debatable. Some recent reports show a 30% drop in the incidence of age-ajusted prostate cancer from 1992 to 1994, adecline (6%) in prostate cancer mortality between 1991 and 1995 in the United States. However, the mortality from other forms of cancer also declined during this time interval. Thus, it remains to be shown whether the decline of prostate cancer mortality can be explained by the increased frequency of PSA-driven therapy during the past decade.
Stage T1a No definitive treatment is recommended currently, although careful follow-up is appropriate. It is critical to ascertain that the patient is truly at stage T1a, and not T1b. This distinction is especially important in patients who are younger than 70 years of age and minght be candidates for curative surgery or radiation therapy. Within 3 months of the initial diagnosis of stage T1a prostate cancer, residual cancer within the prostate should be ruled out by needle biopsy, fine-needle aspiration, or transurethral, resection. If no residual tumor is found, long-term, age- adjusted survival equal to that of the population without cancer can be expected. However, some have advocated more aggressive therapy for patients less than 55 years of age.
Treatment modalities in localized prostate cancer
I. Radical Prostatetomy
- Perineal approach
- Retropublc approach
- Transcoccygeal approach
II Radiation therapy
- External beam alone
- Interstitial radiation
III. Hormone manipulation
- Bilateral orchiectomy
- Estrogen therapy (diethylstilbestrol)
- Progestational agents (Megestrol acetate)
- Luteinizing hormone-releasing hormone (LHRH) analogs (leuprolide, goserlin)
- Luteinizing (cyproterone acetate, flutamide, bicalutamide, nilutamide)
3. Stage T1b Patients with stage T1b disease should be treated aggres sively. At pelvic lymph node dissection, between 30% and 40% of patients will be upstaged to stage N+\D1. Either external-beam radiation therapy or radical prostatectomy may be used in treating stage T1b prostate cancer. Previous TURP has not been an imprdiment to successful radical surgery, in terms of either technical ease or achievement of cure Patients with stage T1b disease are not usually candidates for interstitial irradiation: there is usually insufficient prostatic tissue remaining after TURP for placement of the radioactive seeds. Deferred conserva tive treatment has genrally been a valid option in patients loder than 70 years of age with a low Gleason score, clinically localized prostate caner (stage T1a.) and life expectancies of 10 years or less.
4. Stage T2. A) Radical prostatectomy Patients with stage T2 dissease are ideal candidates for radical prostatectomy of pelvic lymph node dissection rules out lymph node involvement. The PSA and Gleason score may be used together to predict the incidence of organ-confined disease. The incidence of code-positive disease is very low in patients with low-grade tumors (Gleason score<4) and\or a PSA level below 10 ng\mL: pelvic Iymphadenectomy may be omitted in such patients. Radical prostatectomy may be performed via either retropublic, perineal, or transcoccygeal approach. The prostate is removed en bloc along with the seminal vesicles. The bladder neck is reconstructed and anastomosed to the distal membranous urethra. In localized prosltate cancer, radical prostatectomy offers the best chance of long-term disease-free survival Neoadjuvant hormone therapy has been advocated before radical prostatectomy to induce a lower stage, decrease positive surgical margins, and effect a reduction in long term cancer recurrences rates. However, pathologic downstaging and a significant difference with respect to PSA progressin have not been noted. Incontinence following radical prostatectomy is the reincipal complication and has a reported incidence varying from 5% to 25% Impotence from distuption of the nerve supply to the penis during classic radical prostatectomy is common (>80%); however, newer surgical techniques that spare the pelvic nerves have resulted in preservation of potency in 20% to 60% of patients.
|PSA||< 4||5||6||> 7|
B.External-beam radiation therapy achieves survival rates equivalent to those of radical prostatectomy at 5 and 10 years following diagnosis; hlwever, statistics show a definite advantage to radical surgery at 10 to 15 years. Prostate cancers with a higher Gleason grade(>_7) have fared poorly with radiation, and radical surgery has been recommended. The treatment schedule can be tedious-with 6 to 8 weels usually required for delivery. Radiation rherapy offers an alternative treatment in patients who are poor surgical risks or who rafuse surgery. Complications of radiation therpy include proctitis, cystitis, urethral stricture. and erectile impotence, especially in patients with preexisting vascular dissease.
Interstitial irratiation also referred to as Brachytherapy, has become increasingly popular to treat stage T2 disease. Ildine 125 and palladium 103 give good local control of low-volume disease. A recent study from Seattle demonstrated biochemical outcomes comparable with those of radical prostatectomy and external-beam irradiation after 7years (disease-free survival, 79%). Minimal morbidity was reported, with no prostate cancer deaths. All patients; trated with radiation therpy, whether external-beam or interstitial, should be followed carefully. Periodic PSA measurement and rectal examinations are essential for follow-up If residual cancer is demon-strated by bipsy, rhere is high likelihood of future metastases.
A) Ezternal-beam radiothrapy Traditionally. stage T3 disease has been treated with external-beam radiotherapy because of the high incidence (35% to 60% ) of understaging by clinical methods. Pelvic Iymphadenectomy is especially imporatant in this group to determine the best mode of therapy. However, numerous studies have found poor local clntrol as judged by PSA measurement or biopsy after treatment. New three-dimensional radiation that allows higher doses of radiation to be used with reduced complications may improve these results. Also, the use of beoadjuvant hormonal therapy with radiation has been shown to reduce local progression and increase metastasis-free survival with a possible survival advantage. Necause radiation ahd hormonally mediated appoptosis appear to be induced by different mechanisms, their interaction may well be synergistic. addition, therr is a potential reduction in radiation-associated morbidity.
B. Brachyrherpy with external- beam radiation and neoadjuvant bormones has also been explored with good results.
Adjuvant radiotherapy has been advocated for positive-margin disease or a late rising PSA. Possible complications of irraditation of the prostatic bed includes proctitis, cystitis, fistula formation, urinary and or fecal infcontinenece, and edema of the scrotum and lower extremities.
- Hormonal therapy will reduce Psa by 95% and improve symptom free survival, but overall survival has not been affected.
6.Stage N+, M+, or D (Jewett) Metastic prostate cancer remains a therapeutic dilemma for the urologist. Hormonal manipulation will achieve a response in up to 90% patients. However, the timing and method of hormonal therapy remain controversial. Harmonal treatment in general does not appear to improve. Survival but may increase the disease-free interval in patients without symtomatic metastases.
Immediate versus delayed hormonal therapy remains controversial. The rationale for deferring hormonal managment until progression of disease is based on several considerations. Localized prostate cancer is primarily asymptomatic. Hormonal therapy is usually effecacious only for upto 3 years. And studies indicate that 10 year disease-free survival ini patients with grades 1 and 2 tumors is more than 85% although it is only 34% for grade 3 tumors. Approximately 40% of patients die of other causes because of their age at diagnosis (>70 years) On the other hand, recent data, including those from a large randomized trial, suggest that more patients progressed from M0 to M1, disease (p<.001) and that metastatic pain occurred more rapidly in deferred patients. More than twice as many patients required. TURP because of local progression. In addition, pathologic fracture spinal cord compression, ureteral obstruction, and development of extraskeletal metastasis were twice as common in deferred patients. A covariant analytic review of data from the Veterans Administration Co-operative Urological Research Group studies suggests that initiatinig therapy when patients have minimal metastic disease may be beneficial. Delayed hormonal therapy may be appropriate for older patients with a life expectancy of 10 years or less and localized prostate cancer (State T1 or T2) or for patients who value potency over other factors. Early hormonal therapy may be appropriate for younger patients, those with more advanced disease, and patients who do not want the “no treatment” option.
Bilateral Orchiectomy appears to be the most consistent means of endocrine manipulation, Results are immediate, there is virtually no operative morbidity, and patient compliance is not a problem.
Medical castration may be achieved by a variety of agents. See Chapter 15 for discussion of their us in prostate cancer.
Combined androgen blockade is the combination of surgical or medical castration with peripheral antiandrogen blockade in the treatment of advanced prostate cancer. Although not all trials have shown a benefit of combined androgen blockade over conventional therapy, two of the largest controlled trials, the National Cancer Institute (NCI) Intergroup 0036 Study and the Urological Group of the European Organization on Research and Treatment (EORTC) 30853 study, demonstrated statistically signficant prologned survival for patients treated by combined androgen blockade comparaed with those treated by surgical or medical castration alone (particularly for minimal metastatic burden) Combined androgen blockade should be considered in all patinets in whom flare ups must be blocked and patients who have not responded to monotherapy.
Antiandrogens may also be considered as monotherapy (see Chapter 15) Intermittent androgen ablation is a new technique that might improve overall survival by delaying the emergence of androgen-independent clones while improving the overall quality of life. Antiandrogen withdrawl has also been shown to decrease PSA levels. This antiandrogen withdrawal syndrome has been demonstrated with nonsteroidal as well as steroidal (e.g. megestrol) antiandrogen agents. A point mutation in androgen binding receptiors that may sensitize tumor cells to the antiandrogen agent is theorized. Aminoglutethimide and ketoconazole can be used to lower serum testosterone quickly in cases involving spinal cord compression secondary to metastases.
Hormone-resistant disease There is little effective therapy for patients in whom hormonal manipulation has failed. Palliation may be achieved with focal irradiation to metastatic sites in bone. Strontium 89 has been approved for the management of pain arising from skeletal metases. Strontium is a radiopharmaceutical that emits a B – particla and localizes in bone after intravenous injection. Approximately 70% to 80% of patients experience paini relief. Chemotherapy has produced little response., either objective or subjective.
Despite increased efforts at screening for prostate cancer, about 15% of patients with prostate cancer present with advanced-stage disease that is not amenable to either surgical or radiation theraphy. Although significant palliation may be achieved with hormonal therapy, radiotheraphy, or
chemotherapy, survival has been prolonged only minimally
Hormonal Therapy The androgen dependency of the human prostate gland has been appreciated for at least 60 years. In many ways, prostate cancer in the male equivalent of breast cancer in women, especially with respect to the role of hormonal manipulation in advanced disease. The neoplastic prostate cell retains a dependency on androgenic hormones for optimal growth, although this dependence is seldom complete, thus, any agent or procedure that interferes with the production, release, binding, or actions of androgens may potentially inhabit the growth of the prostate cancer cell.
Androgen deprivation continues to be the most frequently used initial treatment for symptomatic metastatic prostate cancer Androgen deprivation may be achieved by bilateral orchiectomy, analogs of GNRH. Bilateral orchiectomy continues to be used – although rarely – incases of poor compliance with medication schedules. Administration of estarogens may be considered when financial barriers preclude obtaining injectable synthetic pituitary inhibitors. Any of these treatment approaches will produce subjective responses in 75% to 80% of patients with symptomatic metastatic prostate cancer; the response can be expected to last approximately 1 year. Estrogens are relatively contraindicated in patients with a history of thromboembolic disease or congestive heart failure. Estrogen is usually administered as diethylstilbestrol at a daily dose of 1 to 3 mg orally. With measurement of serum testosterone levels to monitor effectiveness, the lowest effective dose should be used. Low-dose radiation (900 to 1,200 cGy in three doses) to be breasts should be administered before diethlstilberstrol is initiated to prevent painful gynecomastia. Hormones can be started 2 to 3 days later.
LHRH agonists Leuprolide (Lupron) and goserelin (Zoladex) are synthetic analogs of GnRH; both are available in depot forms that allow convenient monthly, 3-monthly or 4-monthly injections. They appear to be therapeutically equivalent to estrogens, without the cardiovascular complications. LHRH agonists are often administered in conjunction with flutamide. The advantage of this combination is blockade of the LHRH against flare reaction by flutamide and blockade of flutamide gynecomastia by the LHRH agonist.
Other regimens Patients who do not respond initially to hormonal therapy or who relapse after an initial response seldom respond to alternative hormonal treatment. Therapeutic strategies that have been employed include blockade of adrenal androgen production (amino-glutethimide and megestrol acetate) and peripheral androgen blockade by ketoconazole, have been found to inhibit both adrenal and testicular testosterone production. Ketoconazole has produced objective responses in patients with prostate cancer, most often when used as the initial hormone therapy. Another drug that has aroused some interest is suramin, which inhibits cytokine platelet-derived growth factor. It has shown a response rate of better than 40%; the rate of serious side effects has been less then 20% with careful monitoring of plasma drug levels. The results of all these alternative strategies, when employed as salvage therapy, have been disappointing.
B. Cytotoxic chemotherapy
1. Factors hindering the use of chemotherapy in prostate cancer
- Difficulties in quantifying response. Most patients with prostate cancer have disease that is not amenable to measurement by standard response criteria.
- Poor performance status is typical of patients with prostate cancer because of their advanced age and debilitation.
Bone marrow reserve is often limited because of marrow replacement by tumor and previous irradiation. This factor limits patient tolerance of drugs with significant myelosuppressive activities.
Active agents A number of active agents have been identified, including doxorubicin, cyclophosphamide, 5-FU, methotrexate, and cis-plant chemotherapy-hormonal agent combination chemotherapy regimens and chemotherapy-hormonal agent combinations have been evaluated. CRs are rare and objective PRs are uncommon. No single agent has demonstrated clearly superior efficacy against this tumor. Combination chemotherapy has not been shown to be superior to single agents. Chemotherapy has not provided any demonstrable survival benefit in prostate cancer, and median survival is 30 to 40 weeks in most studies; however, considerable pain relief and palliation can be achieved in patients who demonstrate some response.
Specific regimens Given its modest efficacy in this disease, chemotherapy should be offered only if specific and attainable treatment goals such as pain relief can be identified. In view of the lack of demonstrable superiority for combination regimens, single agents should be given preference. Overall responses for these agents range from 15% to 30%. Specific single agents include the following:
- Doxorubicin, 20 mg/m2 IV weekly or 60 mg/m2 IV every 3 weeks
- Methotrexate, 40 mg/m2 IV weekly every 3 weeks
- Cis-platinum, 40 to 60 mg/m2 IV every 3 weeks
- Cyclophosphamide, 600 to 1,000 mg/m2 IV every 3 weeks
- 5-FU, 500 mg/m2 IV weekly.
Toxicity of these agents has been discussed previously. Appropriate dose reductions should be made in patients with limited bone marrow reserve. Doxorubicin is contraindicated in patients with a history of heart disease. In addition, many patients with prostate cancer have considerable renal impairment, precluding the use of cis-platinum and methotrexate.
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