Management of Androgen Deprivation Therapy in Prostate Cancer with Neuroendocrine Differentiation
Yes, continue androgen deprivation therapy (ADT) in prostate cancer with neuroendocrine differentiation, while transitioning primary treatment to platinum-based chemotherapy (cisplatin/etoposide or carboplatin/etoposide). 1
Primary Treatment Strategy
Switch to cytotoxic chemotherapy as the mainstay of treatment:
- Platinum-based regimens (cisplatin/etoposide or carboplatin/etoposide) should be initiated as the primary therapeutic approach for confirmed neuroendocrine differentiation 1
- This represents a fundamental shift from hormone-based therapy to chemotherapy-based management 1
Rationale for Continuing ADT
Maintain castrate testosterone levels despite neuroendocrine transformation:
- The androgen receptor remains active even in castration-resistant disease, and ADT should be continued for life 1
- Castrate levels of testosterone should be maintained while additional therapies (including chemotherapy) are applied 1
- This recommendation applies to all patients with castration-recurrent prostate cancer, including those with neuroendocrine features 1
Key mechanistic consideration:
- While neuroendocrine cells themselves lack androgen receptors and are androgen-independent 2, 3, the surrounding adenocarcinoma component typically remains present and androgen-responsive 2
- Neuroendocrine cells secrete growth factors that support surrounding tumor cells in a paracrine manner 4
- Discontinuing ADT could allow the residual adenocarcinoma component to proliferate 2
Diagnostic Confirmation
Biopsy accessible lesions before changing treatment:
- Patients who fail to respond to ADT, especially those with initial Gleason score 9 or 10, should undergo biopsy of accessible lesions to confirm neuroendocrine differentiation 1
- Look for loss of androgen receptor and PSA expression, with positive staining for neuroendocrine markers (chromogranin A, synaptophysin, neuron-specific enolase) 5, 2
Clinical red flags suggesting neuroendocrine differentiation:
- Lack of response to ADT despite castrate testosterone levels 1
- High-grade disease (Gleason 9-10) at diagnosis 1
- Visceral metastases (particularly liver) 1
- Elevated neuroendocrine markers in serum (chromogranin A) with low or disproportionately low PSA 2
- Rapid progression despite hormonal therapy 6
Treatment Algorithm
Step 1: Confirm castrate testosterone levels
- Verify serum testosterone <50 ng/dL (or <20 ng/dL by modern assays) 1
- If not achieved, optimize ADT before attributing failure to neuroendocrine transformation 1
Step 2: Obtain tissue diagnosis
- Biopsy accessible metastatic lesions for histologic confirmation 1
- Immunohistochemistry for neuroendocrine markers (chromogranin A, synaptophysin, CD56) 5, 2
Step 3: Initiate platinum-based chemotherapy
- Cisplatin/etoposide or carboplatin/etoposide as first-line treatment 1
- Continue LHRH agonist/antagonist or maintain surgical castration 1
Step 4: Consider discontinuing antiandrogens
- If patient was on combined androgen blockade, discontinue the antiandrogen component to assess for antiandrogen withdrawal response 1
- Maintain castration (LHRH agonist/antagonist or orchiectomy) 1
Common Pitfalls to Avoid
Do not continue ADT as monotherapy:
- Neuroendocrine cells are androgen-independent and will not respond to hormonal manipulations alone 2, 3
- Delaying chemotherapy while pursuing additional hormonal therapies wastes valuable time in an aggressive disease 1, 2
Do not rely on PSA for monitoring:
- Neuroendocrine prostate cancer often has low or absent PSA production 1, 2
- Use imaging and clinical assessment rather than PSA kinetics 1
Do not assume all castration-resistant disease is neuroendocrine:
- Most CRPC remains adenocarcinoma and responds to newer hormonal agents (abiraterone, enzalutamide) 1
- Tissue confirmation is essential before abandoning hormone-based approaches 1
Prognosis and Monitoring
Neuroendocrine differentiation indicates aggressive biology: