What is the main role of lowering testosterone with Androgen Deprivation Therapy (ADT) in prostate cancer?

The Role of Androgen Deprivation Therapy in Prostate Cancer

The main role of lowering testosterone with Androgen Deprivation Therapy (ADT) in prostate cancer is to suppress tumor growth and progression by reducing testosterone to castrate levels (<50 ng/dL), as prostate cancer cells are dependent on androgens for their survival and proliferation. 1

Mechanism of Action

ADT works through several key mechanisms:

• Prevents activation of androgen receptors in target cells through either:

  • Reduction in testosterone production (via LHRH agonists/antagonists or surgical castration)
  • Blockade of androgen receptors (via antiandrogens) 2

• LHRH agonists (like leuprolide) initially cause a surge in LH and FSH, followed by downregulation of receptors, leading to decreased testosterone production 3

• LHRH antagonists directly block receptors without the initial surge 4

• The resulting castrate levels of testosterone (typically <50 ng/dL) lead to:

  • Regression of accessory sex organs
  • Suppression of prostate cancer cell growth
  • Potential regression of hormone-sensitive tumors 1, 4

Clinical Applications

ADT serves as:

1. Gold standard treatment for metastatic prostate cancer 1

   • Delays progression of disease
   • Provides symptomatic relief
   • Extends survival in metastatic settings

2. Adjuvant therapy with radiation for high-risk localized or locally advanced disease 1

   • ADT before, during, and after radiation therapy has been shown to prolong survival in selected patients

3. Treatment for biochemical recurrence (rising PSA after definitive treatment) 1

   • May delay appearance of symptoms and metastases
   • Timing remains controversial and should be based on PSA velocity and doubling time

4. Management of locally advanced disease 1, 2

Treatment Options

The primary ADT approaches include:

• Surgical castration (bilateral orchiectomy)

  • Rapid testosterone reduction
  • Permanent effect
  • Lower risk of fractures and cardiovascular complications compared to LHRH agonists 1

• Medical castration

  • LHRH agonists (leuprolide, goserelin)
  • LHRH antagonists
  • Both are equally effective as surgical castration 1

• Combined androgen blockade (CAB)

  • Addition of antiandrogens to castration therapy
  • Provides modest to no benefit over castration alone in metastatic disease 1

Monitoring and Effectiveness

• Adequate suppression of serum testosterone to <50 ng/dL is essential 1
• PSA levels should be monitored to assess treatment response
• Imaging may be required to evaluate disease progression

Considerations and Limitations

• Side effects include:

  • Cardiovascular complications 5, 6
  • Metabolic changes (insulin resistance, dyslipidemia)
  • Bone loss and increased fracture risk
  • Hot flashes, sexual dysfunction, and cognitive changes

• Resistance development:

  • Most patients eventually develop castration-resistant prostate cancer (CRPC)
  • Mechanisms include androgen receptor activation and autocrine/paracrine androgen synthesis 1, 7
  • Secondary hormonal manipulations may be required when resistance develops

• Intermittent vs. continuous ADT:

  • Intermittent ADT may provide similar survival outcomes with improved quality of life 1
  • Close monitoring required during off-treatment periods

Common Pitfalls

1. Inadequate testosterone suppression:

   • Failure to achieve castrate levels (<50 ng/dL) may adversely impact survival 7
   • Regular monitoring of testosterone levels is essential

2. Overuse in low-risk disease:

   • ADT has not shown survival benefit in early-stage, low-risk disease 1
   • Unnecessary exposure to side effects should be avoided

3. Ignoring cardiovascular risk:

   • Cardiovascular risk assessment before initiating ADT is crucial
   • Risk appears highest in elderly patients with recent cardiovascular events 6

4. Neglecting bone health:

   • ADT increases risk of osteoporosis and fractures
   • Bone health monitoring and preventive measures should be implemented

In summary, ADT remains a cornerstone of prostate cancer treatment by effectively lowering testosterone levels to inhibit cancer growth and progression. However, its use must be carefully balanced against potential side effects, with appropriate monitoring and management strategies in place.