What is the recommended dosage and treatment protocol for flutamide (antiandrogen) in prostate cancer?

Flutamide Dosage and Treatment Protocol for Prostate Cancer

The standard recommended dosage of flutamide in prostate cancer is 250 mg taken orally three times daily (750 mg total daily dose) in combination with LHRH agonists for the management of locally confined Stage B2-C and Stage D2 metastatic carcinoma of the prostate. 1

FDA-Approved Indications

Flutamide is specifically indicated for:

• Stage B2-C Prostate Cancer: Treatment should start 8 weeks prior to initiating radiation therapy and continue during radiation therapy, in combination with goserelin acetate implant 1

• Stage D2 Metastatic Prostate Cancer: Flutamide should be initiated with an LHRH agonist and continued until disease progression 1

Evidence Supporting Efficacy

Combination Therapy with Radiation

• In patients with T2-T4 prostate cancer, flutamide (250 mg three times daily) combined with goserelin and radiation therapy significantly improved:

  • Local control (30% vs 42% local failure rate)
  • Disease-free survival (33% vs 21%)
  • Reduced prostate cancer-specific mortality (23% vs 31%) 2

• For intermediate or high-risk locally advanced prostate cancer, androgen suppression before and during external beam radiotherapy significantly improves local control, reduces disease progression, and improves overall survival 2

Combination Therapy with LHRH Agonists

• Flutamide combined with LHRH agonists (total androgen blockade) has demonstrated:
  • Improved disease-specific survival and progression-free survival compared to LHRH monotherapy 3
  • Acceptable safety profile when used in combination therapy 4

Dosing Considerations

While the standard dose is 250 mg three times daily (750 mg/day), some evidence suggests:

• A lower dose of 375 mg/day (125 mg three times daily) may be appropriate in certain populations, particularly when there are concerns about adverse effects 5
• The 375 mg/day dose showed similar objective response rates (85.7%) to higher doses while potentially reducing side effects 5

Treatment Duration

• For Stage B2-C: Start 8 weeks before radiation and continue throughout radiation therapy 1
• For Stage D2 metastatic disease: Continue until disease progression 1
• When used with LHRH agonists for locally advanced disease, treatment duration in trials ranged from 3 months to 3 years 2

Common Adverse Effects and Management

1. Gastrointestinal effects:

   • Diarrhea (occurs in ~15% of patients)
   • Nausea/vomiting
   • Loss of appetite
   • Approximately 2% of patients may require discontinuation due to severe diarrhea 4

2. Endocrine effects:

   • Breast tenderness (particularly common in monotherapy, affecting up to 49% of patients)
   • Gynecomastia (14-19%)
   • To prevent painful gynecomastia, breast irradiation (8-15 Gy in 1-3 fractions) should be given 1-2 weeks before initiating antiandrogen therapy 2

3. Hepatotoxicity:

   • Liver function test abnormalities occur in a small percentage of patients
   • Only 0.8% of patients typically require withdrawal due to liver function changes 4
   • Regular monitoring of liver function is recommended

Treatment Algorithm

1. For locally confined Stage B2-C prostate cancer:

   • Start flutamide 250 mg three times daily with LHRH agonist 8 weeks before radiation
   • Consider prophylactic breast irradiation 1-2 weeks before starting flutamide
   • Continue through completion of radiation therapy
   • Monitor for side effects, particularly diarrhea and liver function

2. For Stage D2 metastatic prostate cancer:

   • Start flutamide 250 mg three times daily concurrently with LHRH agonist
   • Continue until disease progression
   • Monitor PSA levels, clinical symptoms, and imaging to assess response
   • Regular liver function monitoring is essential

3. Dose adjustment considerations:

   • If significant side effects occur, particularly diarrhea or hepatotoxicity, consider dose reduction to 375 mg/day (125 mg three times daily) before discontinuation 5, 3
   • If severe adverse effects persist, discontinue flutamide while maintaining LHRH agonist therapy

Monitoring Recommendations

• PSA levels: Regular monitoring to assess treatment response
• Liver function tests: Regular monitoring due to potential hepatotoxicity
• Clinical assessment for adverse effects, particularly gastrointestinal symptoms and breast tenderness
• After radical treatment, follow-up visits should occur at 3 months initially, then yearly 2

Flutamide is now considered a second-line antiandrogen option in most contemporary guidelines, with newer agents like enzalutamide and apalutamide showing improved outcomes in recent clinical trials 2.