Prostate Cancer

Philip W. Kantoff, M.D.
Harvard Medical School

Definition/Key Clinical Features
Differential Diagnosis
Best Tests
Best Therapy
Best References

Definition/Key Clinical Features

• The most commonly diagnosed noncutaneous malignancy in men in the U.S.
• The vast majority are adenocarcinomas
• African Americans have the highest incidence
• Tends to spread to lymph nodes and bone

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Differential Diagnosis

• Benign prostatic hyperplasia
• Chronic prostatitis

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Best Tests

• Goal is to detect organ-confined prostate cancer, which is potentially curable with definitive local therapy
• Optimal screening uses both the prostate-specific antigen (PSA) test and the digital rectal examination (DRE)
• DRE inadequate by itself because most cancers detectable by DRE are not organ-confined and are therefore incurable
• PSA testing
• Can detect prostate cancer an average of 5.5 yr before clinical detection
• Detection of clinically insignificant cancers may lead to unnecessary treatment
• Specificity of an elevated PSA is low
• Conditions such as benign prostatic hyperplasia, acute prostatitis, seminal ejaculation, and genitourinary instrumentation can increase PSA level
• Most men with serum PSA > 10 ng/ml have prostate cancer, likely to be non-organ-confined
• Biopsy in men with serum PSA 4–10 ng/ml usually reveals benign prostatic hyperplasia (BPH) rather than prostate cancer
• Strategies to distinguish malignancy from BPH in men with serum PSA 4–10 ng/ml
• Age-specific serum PSA reference ranges (< 50 yr: ≤ 2.5 ng/ml; 50–59 yr: ≤ 3.5 ng/ml; 60–70 yr: ≤ 4.5 ng/ml; > 70 yr: ≤ 6.5 ng/ml)
• Ratio of serum PSA level to volume of prostate gland (PSA density [PSAD]); in general, patients with cancer have a higher PSAD
• Determine free PSA level (percentage of PSA that is unbound to serum proteins); in men with elevated serum PSA, cancer is more likely when the percentage of free PSA is low
• Men with a PSA change ≥ 2 ng/ml in the year before diagnosis have a 15% 10-yr mortality; less dramatic PSA changes indicate a negligible mortality
• ACS recommendation
• Men > 50 yr with a life expectancy of > 10 yr: annual DRE and PSA test
• High-risk men (i.e., African Americans and men with family history of prostate cancer): annual screening beginning at age 40 yr

• Biopsy, guided by transrectal ultrasonography
• Further biopsies if prostate intraepithelial neoplasia is present
• Histologic grading
• Gleason score: tumors are graded from 1 (least malignant) to 5 (most malignant) on the basis of architectural patterns in the examined tissue; grades reflecting the two most common architectural patterns are added to create the Gleason score
• Correlates with clinical prognosis and is used in stratifying patients
• Most tumors are Gleason 6 or 7
• Clinical staging
• Useful for distinguishing between localized and locally advanced tumors, but otherwise of limited value in judging curability or extent of disease or in determining appropriate treatment
• TNM classification
• T1 and T2 tumors: localized, detected by transurethral resection, generally indolent
• T3 and T4 tumors: rarely cured by surgery or radiation therapy alone
• Multifactorial staging
• Combines clinical stage, serum PSA level, and Gleason score
• Most clinically useful way to stratify by prognosis
• Risk of biochemical (PSA) relapse after local therapy
• Low (> 85% 5-yr PSA failure-free survival): T1c or T2a, and PSA ≤ 10 ng/ml, and Gleason score ≤ 6
• Medium (50% 5-yr PSA failure-free survival): T2b, or PSA > 10 and ≤ 20 ng/ml, or Gleason score = 7
• High (22% 5-yr PSA failure-free survival): T2c, or PSA > 20 ng/ml, or Gleason score ≥ 8
• Staging based on imaging
• Not useful for most patients
• Bone scans to assess skeletal involvement and CT or MRI scans to assess regional lymph nodes may be useful in men with serum PSA > 10 ng/ml, Gleason score 8–10, or locally advanced cancer (T3 or T4)

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Best Therapy

• Risk of prostate cancer mortality
• Gleason score ≥ 7 and age ≤ 74 yr: significant risk
• Gleason score ≤ 6 at any age: minimal to modest risk

• Treatment decisions are based on patient and physician preferences, attitudes toward treatment-related side effects, and comorbidity
• Radical prostatectomy: side effects include urinary incontinence and, frequently, erectile dysfunction
• Radiation therapy: side effects include erectile dysfunction and rectal injury resulting in changes in bowel function
• Brachytherapy: easily administered, apparently favorable toxicity profile, promising cancer-control rates; implant placement may leave cold spots where cancer persists
• External-beam radiation: the standard dose may be insufficient to eradicate all cancer

• Low-risk patients: outcomes are generally excellent, regardless of therapy
• Intermediate-risk patients
• Higher likelihood of occult metastatic disease
• Surgery is curative in about 50% of cases, but many will require further therapy because of recurrent or persistent local cancer or because of distant metastases
• Concomitant androgen ablation in conjunction with radiation may be beneficial
• High-risk patients
• Highest likelihood of occult metastatic disease
• Local therapy alone is rarely curative, so the morbidity of radical prostatectomy is difficult to justify
• Many such patients receive androgen ablation followed by external-beam radiation therapy, although long-term results are poor

Salvage Treatment

• Relapse after radical prostatectomy
• Patients who can be successfully treated with radiation therapy are those with organ-confined cancer at the time of initial treatment, increased PSA levels occurring > 2 yr after surgery, and a serum PSA level < 1 ng/ml at time of salvage therapy
• Relapse after initial radiation therapy
• Salvage radical prostatectomy is associated with very high morbidity
• Before either salvage treatment, restage with bone scan, CT scan, MRI, and possibly scintigraphy

• Standard initial treatment for advanced prostate cancer
• Side effects
• Hot flashes
• Loss of libido
• Impotence
• Gain of adipose tissue
• Loss of muscle and bone mass
• Likely modest increase in cardiovascular events
• May slow progression of disease and prolong survival when begun with primary treatment
• Different modalities have equivalent impact on survival, although antiandrogen monotherapy is inferior to the others in patients with metastases
• Orchiectomy
• Luteinizing hormone-releasing hormone (LHRH) agonists leuprolide or goserelin, administered either monthly or every 3 or 4 mo
• Antiandrogens (flutamide, bicalutamide, nilutamide), mostly used with chemical or surgical castration
• Disease typically recurs, indicated by rise in serum PSA level
• Duration of response is ~ 12–18 mo in patients with overt metastatic disease and much longer in men without metastases
• Estrogen: side effects include gynecomastia and thromboembolic phenomena

• Docetaxel plus prednisone: standard chemotherapy for metastatic prostate cancer
• Mitoxantrone plus a corticosteroid: has produced improvements in quality of life but not in survival
• Taxanes (paclitaxel, docetaxel): longer survival has been demonstrated for treatment with docetaxel than with mitoxantrone plus prednisone

• Analgesics (NSAIDs and narcotics)
• External-beam radiation therapy
• Radiopharmaceuticals (strontium-89, samarium-153–labeled EDTMP)
• Generally well tolerated
• Progressive marrow suppression may occur with repeat dosing

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Best References

Bill-Axelson A, et al: N Engl J Med 352:1977, 2005 [PMID 15888698]

Partin AW, et al: JAMA 277:1445, 1997 [PMID 9145716]

Thompson IM, et al: N Engl J Med 350:2239, 2004 [PMID 15163773]

November 2006