What is the dosing regimen and usage of Goserelin (Leuprolide) for hormone-sensitive cancers?

Goserelin Dosing and Usage in Hormone-Sensitive Cancers

Standard Dosing Regimen

Goserelin is administered as a 3.6 mg subcutaneous depot injection every 28 days (4 weeks), providing continuous drug release at approximately 120 mcg/day throughout the dosing interval. 1, 2

• The depot formulation is preloaded in a 16-gauge needle syringe and injected subcutaneously, typically in the anterior abdominal wall 1
• A 10.8 mg depot formulation is also available for 3-month (12-week) administration intervals 3
• Peak plasma concentrations occur between days 8-22, with sustained release throughout the 28-day period 1

Mechanism and Pharmacodynamics

Goserelin initially stimulates luteinizing hormone (LH) and follicle-stimulating hormone (FSH) release for 1-2 weeks, followed by receptor downregulation that achieves chemical castration within 2-4 weeks of initiation. 1, 2

• In males, testosterone levels fall to castrate range (typically <50 ng/dL) within 3-4 weeks and remain suppressed throughout continuous therapy 1, 2
• In females, estradiol is suppressed to postmenopausal levels within 3 weeks of initial administration 1
• Castrate levels of testosterone are maintained for the duration of therapy in clinical trials exceeding 2 years of follow-up 1

Clinical Applications by Cancer Type

Prostate Cancer

For localized high-risk prostate cancer (T2c-T4 or high-grade disease), goserelin 3.6 mg every 4 weeks combined with radiation therapy significantly improves survival outcomes compared to radiation alone. 4

Localized Disease with Radiation Therapy:

• Short-term regimen: 2 months before and during radiation therapy (total 4 months) 4
• Long-term regimen: For advanced local disease (T2c-T4), continuation for 2-3 years after radiation significantly improves disease-free survival (46.4% vs 28.1% at 5 years, p<0.0001) 4
• Very high-risk disease (T3-T4, PSA >40, or Gleason 8-10): 24-36 months of goserelin combined with radiation therapy 4

Specific Evidence-Based Protocols:

• RTOG 86-10 protocol: Goserelin 3.6 mg every 4 weeks plus flutamide 250 mg three times daily, initiated 2 months before and continued during radiation, reduced 8-year local failure from 42% to 30% (p=0.016) 4
• RTOG 92-02 protocol: Extended therapy (2 years total) versus short-term (4 months) showed superior 5-year disease-free survival (46.4% vs 28.1%, p<0.0001) in patients with bulky disease 4
• EORTC trial: Goserelin 3.6 mg every 4 weeks for 3 years starting on first day of radiation improved 5-year overall survival from 62% to 78% (p=0.0002) 4

Metastatic Hormone-Sensitive Prostate Cancer:

Continuous androgen deprivation therapy with goserelin must be maintained indefinitely throughout the disease course, even when the disease progresses to castration-resistant status. 5

• Goserelin produces objective response rates of approximately 75% in previously untreated metastatic prostate cancer 2, 6
• Critical principle: ADT should never be discontinued in metastatic disease, as testosterone suppression remains essential even when adding additional systemic therapies 5
• Discontinuation leads to rapid testosterone recovery within weeks to months, with accelerated disease progression and risk of complications including pathologic fractures and spinal cord compression 5

Breast Cancer (Premenopausal Women)

In premenopausal women with hormone-receptor-positive early breast cancer, goserelin 3.6 mg every 28 days is at least as effective as CMF chemotherapy and can be combined with tamoxifen for enhanced efficacy. 7

• Objective response rates of 30-45% in premenopausal metastatic breast cancer, comparable to surgical ovariectomy 2, 8
• In metastatic disease, median time to progression ranges from 27-59 weeks depending on response category 8
• Overall response rate (complete + partial remissions) of 44.9% in premenopausal metastatic breast cancer patients 8

Combined Androgen Blockade

When combining goserelin with antiandrogens (combined androgen blockade), the addition of nonsteroidal antiandrogens provides a statistically significant but modest survival benefit over goserelin monotherapy. 4

Recommended Combinations:

• Flutamide: 250 mg three times daily with goserelin 4
• Bicalutamide: 50-80 mg once daily (longer half-life allows once-daily dosing) 4
• Cyproterone acetate: 50 mg three times daily, started 1 week before goserelin to prevent tumor flare 4

Evidence for Combined Blockade:

• Meta-analysis showed hazard ratio of 0.92 (95% CI 0.86-0.98) for all-cause mortality with nonsteroidal antiandrogen addition 4
• Benefit appears primarily after 5 years of follow-up (HR 0.871,95% CI 0.805-0.942) 4
• Combined therapy increases risk of diarrhea (10% vs 2%), GI pain (7% vs 2%), and ophthalmologic events (29% vs 5%) 4

Critical Management Considerations

Tumor Flare Prevention

The initial testosterone surge during the first 1-2 weeks of goserelin therapy can cause disease flare in up to 4% of patients with advanced prostate cancer. 4, 6

• Flare manifests as worsening bone pain, urinary obstruction, or spinal cord compression 4
• Prevention strategy: Initiate antiandrogen therapy (cyproterone 50 mg TID or flutamide 250 mg TID) 1 week before first goserelin injection 4
• Surgical castration remains preferred for patients at immediate risk of spinal cord compression or ureteric obstruction 6

Duration of Therapy

Goserelin therapy should be continued indefinitely in metastatic disease as long as clinical benefit persists, regardless of PSA progression or isolated site progression. 5

• Therapy may continue even with slow PSA progression if disease-related symptoms remain controlled 5
• Discontinuation should only be considered for: severe intolerable side effects outweighing cancer control benefits, very limited life expectancy from other causes, or explicit patient choice for comfort-focused care accepting rapid progression 5
• Testosterone and gonadotropin levels return to pretreatment values within 12 weeks after the last injection in most cases 1

Common Adverse Effects

Hot flushes occur in the majority of patients (reported in 19.6-31.7% as adverse drug reactions), along with loss of libido, as direct consequences of sex hormone suppression. 4, 1

• Long-term castrate testosterone levels cause osteopenia, hypercholesterolemia, weight gain, mood changes, and cognitive effects 4
• Gynecomastia and breast pain occur in up to 39% of patients on antiandrogen therapy 4
• Late GI toxicity (grade 3) increases modestly with long-term therapy (2.6% vs 1.2% with short-term) 4

Special Populations

No dose adjustment is required for elderly patients or those with hepatic or renal impairment when using the depot formulation. 1, 3

• Elimination half-life increases from 2-4 hours to 12.1 hours in severe renal impairment, but depot release rate remains the primary determinant of drug exposure 1, 3
• Pharmacokinetics are unaffected by moderate hepatic impairment (transaminases <3x upper limit of normal) 1
• Total body clearance is significantly higher in females (163.9 L/min) compared to males (110.5 L/min), but this does not require dose adjustment 1

Practical Administration Points

• Inject subcutaneously into anterior abdominal wall using the preloaded SafeSystem syringe 1
• The biodegradable lactide-glycolide copolymer matrix releases drug slowly for the first 8 days, then more rapidly for the remaining 20 days 1
• No clinically relevant drug accumulation occurs with monthly administration 1, 3
• Isolated elevations in estradiol may occur in 10% of treated women despite overall suppression 1