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Prostate Cancer

Table of Contents
1 Disease Overview
        1.1 Risk Factors and Prevention
        1.2 Screening
        1.3 History, Symptoms and Signs
        1.4 Diagnosis and Tumour Assessment
2 Staging
3 Stage Grouping
4 Treatment Modalities
        4.1 Active Surveillance
        4.2 Surgery
        4.3 Radiation
        4.4 Hormone Therapy
        4.5 New Modalities for Prostate Cancer
5 Follow-up
        5.1 Treatment of Rising PSA
        5.2 Clinical Trials
6 Pivotal Trials

Disease Overview

    It is estimated in 2014 in Canada 23,600 men will be diagnosed with prostate cancer and 4,000 will die from metastatic prostate cancer. Autopsies show that 70% of men aged 80 and older have occult prostate cancer. As some prostate cancers develop late in life, the risk of death from noncancer-related causes may exceed that of the cancer.

Risk Factors and Prevention

Risk factors include the following:

  • Older age
  • Family history
  • Race: prostate cancer is more common in black men
  • Obesity
  • High-fat diet
  • Smoking

Screening

    Routine screening identifies many prostate cancers. The value of routine screening is still controversial, as studies have not proven an increase in survival.

  • Digital rectal examination (DRE): This examination searches for abnormal texture, size and/or shape of the prostate.
  • Prostate specific antigen (PSA): This non-specific blood test may be elevated in infection, inflammation, benign prostatic hypertrophy, or malignancy.

History, Symptoms and Signs

    Early-stage prostate cancer may have no symptoms. More advanced disease may be associated with urinary problems, such as hematuria or urinary obstruction; blood in the semen; bone pain; pelvic pain; and lower limb edema. Findings of abnormal external anal sphincter tone may indicate spinal cord compression from bone metastases.

Diagnosis and Tumour Assessment

    Transrectal ultrasound may be used if screening tests or symptoms suggest malignancy. Prostate biopsy is performed, and the tumour grade (Gleason score) can determine the aggressiveness and subsequent treatment of the cancer. PSA (prostatic specific antigen) levels are also important. Additional testing, which may include a bone scan, ultrasound, CT scans, and MRI can determine whether the cancer has spread, and can be used for tumour staging.


Staging


Stage Grouping


Treatment Modalities

    The most appropriate treatment options are determined based on the tumour grade, stage, patient age, and patient preferences. Over the last five years there are many options available in prostate cancer and it should be personalized, patient-centered, and multidisciplinary. Patients should also be encouraged to participate in clinical trials.

Active Surveillance

    Active surveillance, or watchful waiting, may be appropriate for a small, low-grade, asymptomatic early-stage cancer, or for a man with other serious health problems or advanced age. Active surveillance typically involves regular monitoring with PSA, DRE, and additional prostate biopsies. The main risk associated with active surveillance is tumour growth resulting in disease that is difficult to treat.

Surgery

    Prostatectomy may be performed through a retropubic or perineal incision, or by a laparoscopic procedure, which may be robotically assisted. Erectile dysfunction and urinary incontinence are the main associated complications. Depending on the tumour size and characteristics, a nerve-sparing procedure, which reduces the risk of complications, may be feasible.

Radiation

    Radiotherapy for prostate cancer can be delivered by external beam radiation or by brachytherapy. Radiation side effects include urinary and rectal problems and erectile dysfunction. Radiation can be used for any stage of prostate cancer.

Hormone Therapy

    Prostate cancer is stimulated by testosterone, and hormone therapy can kill prostate cancer cells or slow their growth. Hormone therapy is also known as androgen deprivation therapy (ADT). In early-stage prostate cancer, hormonal therapy may be used before radiation therapy to shrink the tumour. Hormonal therapy may also be used after surgery or radiation to slow the growth of any remaining cancer cells. In more advanced prostate cancer, hormone therapy may be used in conjunction with radiation.

    Medical hormonal therapy includes luteinizing hormone-releasing hormone (LH-RH) analogues, antagonists and anti-androgens. Both LH-RH analogues and antagonists suppress testosterone levels, whereas anti-androgens block the action of testosterone at the cellular level. Antifungal agents produce a response similar to anti-androgens. Typically, an anti-androgen is given before or together with an LH-RH agent. Orchiectomy lowers testosterone levels as effectively as medical therapy, but at a faster rate.

    Side effects of hormonal therapy include erectile dysfunction, reduced libido, loss of muscle and bone mass, weight gain and hot flashes.

Systemic Therapy for Prostate Cancer

    For patients who relapse after treatment of organ confined disease or those who present with metastatic disease, testosterone suppression with hormone therapy is the foundation of therapy. The initial treatment of metastatic disease androgen ablation is achieved either surgically or medically.

    Lowering testosterone and its precursors and altering the androgen receptor axis was the first method discovered that could control this disease. Either modality should result in reduction in testosterone to levels less than 50 ng/dl, resulting in prostate tumour regression. Clinical response to androgen blockade is manifested by decline in serum PSA, relief in pain from bone metastases and improvement in neurologic symptoms from spinal cord compression when combined with steroids and radiation. Despite initial clinical and symptomatic improvement, nearly all men will progress to castration resistant prostate cancer.

    Recent practice changing study compared androgen deprivation therapy (ADT) alone vs ADT plus docetaxel chemotherapy in men with newly diagnosed prostate cancer. The men could have received local therapy for prostate cancer in the past, although two thirds of them had not. They also could have received hormone therapy in the past.

    The study found that overall survival was improved significantly, by about 14 months, in the combination-therapy group. When they looked at the high-risk patients - those who had either 4 bone lesions or visceral metastases, the overall improvement in survival was 17 months. There was also a delay in time to castrate-resistant disease. The study has not shown a statistically significant benefit in the men who had lower-risk disease.

    These findings are extremely important and are game-changing in terms of managing men with newly diagnosed prostate cancer. The treatment was well tolerated, with 6% developing febrile neutropenia and 1% with either sensory or motor changes neurologically. Overall there was only 1 treatment-related death in the men who received the chemotherapy.

    Castration-resistant prostate cancer (CRPC) is defined as progression of disease either biochemically or objectively, despite castrate testosterone levels. Median survival of CRPC is 9-12 months.

    Chemotherapy may be an option for tumours that are non-responsive to hormonal therapy, in metastatic CRPC. Nonetheless, chemotherapy showed significant improvements in survival in CRPC patients. It is palliative and the chemotherapy agents used are mitoxantrone, prednisone, and docetaxel.

    Despite castrate levels of testosterone, the androgen receptor remains a target for therapy in these patients. Two drugs are available by special access programs Abiraterone (zytiga) and Enzalutamide. Their mechanism of action is shown in the diagram. Abiraterone acetate is converted in vivo to abiraterone, an androgen biosynthesis inhibitor, that inhibits 17 a-hydroxylase/C17,20-lyase (CYP17). This enzyme is expressed in testicular, adrenal, and prostatic tumor tissues and is required for androgen biosynthesis.


Follow-up

    Follow-up includes monitoring of PSA levels, as PSA may rise before any symptoms of recurrence are noted.

  • In patients treated with curative intent, a history and physical examination including digital rectal exam (DRE) should be performed every six months for five years, and then annually thereafter.
  • PSA every six months for five years, and then annually.
  • Routine bone scan and other imaging studies not recommended unless clinically indicated.

Treatment of Rising PSA

Treatment of rising PSA depends on the initial therapy used.

  • Initial radiation: Prostatectomy is often performed if the cancer has not spread outside the prostate. Cryotherapy may also be performed.
  • Initial surgery: Radiation is used for recurrence after surgery.
  • Other: Men who cannot have radiation, surgery or cryotherapy may be treated with ADT.

Clinical Trials

    Options for hormone-refractory metastatic prostate cancer are limited. Clinical trial participation may involve chemotherapy combined with hormonal therapy.


Pivotal Trials

Southwest Oncology Group, Berry DL, Moinpour CM, et al. Quality of life and pain in advanced stage prostate cancer: results of a Southwest Oncology Group randomized trial comparing docetaxel and estramustine to mitoxantrone and prednisone. J. Clin Oncol. 2006;24(18):2828-2835