69 Advanced Stage Prostate Cancer: Controversies in Management
In this chapter, we go into more detail’s about the following controversies in management of metastatic prostate cancer:
• Timing of initiation of systemic therapy for patients with elevated prostate-specific antigen (PSA) as only evidence of disease when local therapies are no longer available.
• Timing of initiation of therapy for patients with asymptomatic low-volume metastases.
• The role of first-generation antiandrogens in castration-sensitive disease.
TIMING OF INITIATION OF THERAPY FOR PATIENTS WITH ELEVATED PSA AS ONLY EVIDENCE OF DISEASE
Case 1: A 74-year-old male was found to have Gleason’s 10 prostate cancer after evaluation for elevated PSA detected in screening. He underwent prostatectomy with evidence of extraprostatic extension and negative margins. He underwent adjuvant radiation and proceeded with surveillance. PSA went from less than 0.06 ng/mL to 5.1 ng/mL. Should you recommend androgen ablation therapy?
Patients with prostate cancer who have persistently elevated PSA despite surgical treatment or radiation are considered to have persistent disease. If salvage therapy is not an option, the next question is whether the patient should receive systemic therapy with androgen deprivation therapy (ADT). 70While earlier initiation might prevent prostate cancer-related morbidity and improve survival, in some cases disease can be very indolent and ADT has potential adverse effects as well. Unfortunately, there are no randomized trials concluded that have addressed this question.
In a natural history study of 201 patients on ADT with PSA progression and no radiographic evidence of metastases, median bone-metastasis-free survival was 30 months. Thirty-three percent of patients developed bone metastases at 2 years. Predictors of shorter time to bone metastasis and overall survival (OS) were baseline PSA greater than 10 ng/mL and PSA doubling time of 10 months (1). If clinical trial is not an option, these factors may be useful in making the decision about starting ADT in patients with PSA-only relapse even in the ADT-naive setting. The Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) database in 2012 described a series of 2,022 patients with PSA only relapse who had not been treated with ADT. 34.8% of patients had a Gleason score ≥7. After adjusting for poor prognostic factors (Gleason score, PSA velocity), there was no significant difference in OS or prostate cancer specific mortality between patients who started within 3 months of diagnosis or patients who started 2 or more years later or when they presented with metastasis, symptoms, or short PSA doubling time (defined as 6 months or less for PSA <10 ng/mL) (2). Mean time to progression was 35.8 months.
If ADT is started for these patients, there is also the consideration about whether to administer it continuously or intermittently, which is addressed further in the “Intermittent Androgen Ablation in Metastatic Prostate Cancer” subchapter.
TIMING OF INITIATION OF THERAPY FOR PATIENTS WITH ASYMPTOMATIC LOW-VOLUME METASTASES AND USE OF FIRST-GENERATION ANTIANDROGENS IN CASTRATION SENSITIVE METASTATIC PROSTATE CANCER
Case 2: A 63-year-old male was found to have a PSA of 48 ng/mL after screening evaluation. A CT scan showed evidence of right pelvic bone metastasis, with uptake on a 71nuclear bone scan. Biopsy of a bone lesion was consistent with prostate cancer. The patient is otherwise asymptomatic.
Question 1: Should you recommend ADT?
The study of this issue has been limited by heterogeneity in the populations included in clinical trials, different triggers on initiation of ADT, and the fact that some patients do not defer therapy as originally planned (3). Also, many of the trials did not take into account prognostic factors (Gleason score, PSA response, PSA doubling time, life expectancy) into the decision-making progress. Also, while survival is a desired outcome, other factors like disease morbidity have not been consistently examined. With these limitations known, a meta-analysis looking at this question has concluded that early ADT was associated with a decrease in prostate cancer-related death, without a benefit in OS. More clinical trials are needed to answer this question; however, the information suggests that initiation of therapy should be individualized for each patient.
Question 2: Would you recommend a first-generation antiandrogen monotherapy or combined androgen blockade to this patient?
First-generation antiandrogens (e.g., bicalutamide, flutamide, nilutamide) are competitive inhibitors of androgens. They are typically recommended as initial bridging with a gonadotropin releasing hormone (GnRH) agonist and/or after disease progression to medical or surgical castration (castration-resistant disease) (3). A meta-analysis looking at the question of using castration or antiandrogen therapy alone as initial therapy for castration-sensitive prostate cancer found a trend toward shorter OS with antiandrogen monotherapy, although it was not statistically significant (hazard ratio [HR] 1.22, 95% confidence interval [CI] 0.99–1.40) (4). Although some studies have shown a progression free survival benefit of castration combined with antiandrogens as initial therapy (combined androgen blockade), it risks higher toxicity, and the benefit has not been consistently reproduced in clinical trials. Because of this, combined androgen blockade is not widely used (5).