What is the best course of treatment for a patient with metastatic prostate cancer to bone, elevated Carcinoembryonic Antigen (CEA) and Alpha-Fetoprotein (AFP), and now elevated Prostate-Specific Antigen (PSA)?

Management of Metastatic Prostate Cancer with Elevated PSA, CEA, and AFP

For a patient with metastatic prostate cancer to bone who now presents with elevated PSA along with elevated CEA and AFP, immediate continuous androgen deprivation therapy (ADT) should be initiated, and the patient should be evaluated for anaplastic/neuroendocrine features given the atypical tumor marker profile. 1

Critical Diagnostic Considerations

The combination of elevated CEA and AFP alongside PSA in metastatic prostate cancer is highly concerning for undifferentiated or anaplastic prostate cancer with neuroendocrine features. 1 This rare variant has distinct clinical implications:

• PSA is not a reliable indicator of disease activity in patients with undifferentiated metastatic prostate cancer, which often presents with neuroendocrine features and predominant visceral metastases. 1
• A case report documented prostate cancer producing CEA (3,990 ng/ml) and CA19-9 with low PSA levels, demonstrating that these atypical markers can indicate aggressive disease despite low PSA. 2
• Constitutional symptoms (weight loss, pain, loss of appetite) indicate aggressive disease biology and high tumor burden, even when conventional imaging may appear stable. 3

Immediate Treatment Approach

First-Line Systemic Therapy

Immediate continuous castration (ADT) is the preferred treatment for metastatic hormone-naïve prostate cancer. 1

However, given the atypical presentation with elevated CEA/AFP suggesting anaplastic features, early docetaxel chemotherapy should be strongly considered even if the patient is asymptomatic, as this population benefits from early cytotoxic therapy. 1

Specific indications for early docetaxel in this case include:

• Anaplastic prostate cancer features (elevated CEA/AFP). 1
• Rapidly rising PSA, especially after short-term response to ADT. 1
• Presence of visceral metastases (if present). 1

Recommended Regimen

Docetaxel 75 mg/m² every 3 weeks combined with continuous ADT is the standard regimen with proven overall survival benefit. 1, 4

• An antiandrogen should be given for 3-4 weeks when starting ADT with an LHRH agonist to counteract testosterone flare. 1
• Prednisone 5 mg twice daily should be administered continuously with docetaxel. 4
• The recommended duration is up to 10 cycles (approximately 30 weeks). 4

Alternative Considerations for Intensified Therapy

For patients with metastatic hormone-sensitive prostate cancer at first presentation who are fit enough, docetaxel combined with ADT should be considered the standard of care. 5

More recent evidence supports adding androgen receptor signaling inhibitors (ARSIs) to ADT:

• Enzalutamide plus leuprolide demonstrated significant improvement in radiographic progression-free survival (hazard ratio 0.39) and overall survival (hazard ratio 0.66) compared to placebo plus ADT in the ARCHES trial. 6
• Triplet therapy (ARSI + docetaxel + ADT) has the highest likelihood of improved overall survival in patients with metastatic hormone-sensitive prostate cancer, irrespective of performance status. 7

Monitoring Strategy

PSA Monitoring Limitations

In this patient with elevated CEA/AFP, PSA monitoring alone is insufficient. 1

• Clinical assessment and recording of symptoms should be prioritized over PSA values. 1
• Early PSA increases after starting docetaxel (within 12 weeks) should be ignored when determining progression. 1
• PSA response assessment should be delayed until approximately 12 weeks. 1

Imaging Surveillance

• Initial imaging with bone scan and CT/MRI of abdomen and pelvis is strongly recommended. 1
• Systematic imaging surveillance is not mandatory in absence of PSA rise or cancer-related symptoms in typical cases, but given the anaplastic features, more frequent imaging is warranted. 1
• Follow-up should include clinical assessment, testosterone levels, and screening for cardiovascular disease and metabolic syndrome. 5

Bone-Targeted Therapy

Concomitant bone-targeting therapy with denosumab or bisphosphonates is NOT recommended for metastatic hormone-naïve prostate cancer. 1

However, once the patient progresses to castration-resistant disease:

• Zoledronic acid 4 mg IV every 3 weeks can reduce skeletal-related events (33% vs 44% at 15 months, p=0.02). 1
• Denosumab is superior to zoledronic acid in preventing skeletal-related events in metastatic castration-resistant prostate cancer. 1

Critical Pitfalls to Avoid

1. Do not rely solely on PSA monitoring in patients with elevated CEA/AFP, as these markers suggest anaplastic features where PSA is unreliable. 1

2. Do not delay docetaxel in patients with anaplastic features or rapidly rising PSA—early chemotherapy improves outcomes in this population. 1

3. Do not use intermittent androgen deprivation in metastatic hormone-naïve disease outside clinical trials. 1

4. Do not misinterpret early PSA rises during docetaxel therapy as treatment failure—wait until 12 weeks for response assessment. 1

5. Do not add bone-targeting agents (bisphosphonates/denosumab) at initial diagnosis of metastatic hormone-naïve disease, as this provides no benefit and adds toxicity. 1

Prognosis and Quality of Life Considerations

• Median overall survival for metastatic prostate cancer with bone involvement ranges from 18-36 months once metastases are confirmed. 3
• Constitutional symptoms already present indicate significantly impaired quality of life. 3
• The goal of treatment shifts from curative to preventing skeletal-related events and prolonging survival. 3
• Novel systemic therapies benefit overall survival irrespective of performance status, so worse performance status should not discourage treatment intensification. 7