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Stage IV Prostate Cancer Treatment

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    LH-RH agonists or antiandrogens

    Approaches using LH-RH agonists or antiandrogens in patients with stage IV prostate cancer have produced response rates similar to other hormonal treatments.[4,27]

    Evidence (LH-RH agonists or antiandrogens):

    1. In a randomized trial, the LH-RH analog leuprolide (1 mg subcutaneously every day) was found to be as effective as DES (3 mg orally every day) in any T, any N, M1 patients, but caused less gynecomastia, nausea and vomiting, and thromboembolisms.[5]
    2. In other randomized studies, the depot LH-RH analog goserelin was found to be as effective as orchiectomy [6,28,29] or DES at a dose of 3 mg per day.[27] A depot preparation of leuprolide, which is therapeutically equivalent to daily leuprolide, is available as a monthly or 3-monthly depot.
    3. Castration has been shown to be superior to monotherapy with bicalutamide.[30]
    4. A small, randomized study comparing 1 mg DES orally 3 times per day with 250 mg of flutamide 3 times per day in patients with metastatic prostate cancer showed similar response rates with both regimens but superior survival with DES. More cardiovascular and/or thromboembolic toxic effects of borderline statistical significance were associated with DES treatment.[31][Level of evidence: 1iA] A variety of combinations of hormonal therapy have been tested.

    Maximal androgen blockade (MAB)

    On the basis that the adrenal glands continue to produce androgens after surgical or medical castration, case series studies were performed in which antiandrogen therapy was added to castration. Promising results from the case series led to widespread use of the strategy, known as MAB or total androgen blockade. Subsequent randomized, controlled trials, however, cast doubt on the efficacy of adding an antiandrogen to castration.

    Evidence (MAB):

    1. In a large, randomized, controlled trial comparing treatment with bilateral orchiectomy plus either the antiandrogen flutamide or placebo, no difference in OS was reported.[32][Level of evidence: 1iA]
      • Although it has been suggested that MAB may improve the more subjective endpoint of response rate, prospectively assessed quality of life was worse in the flutamide arm than in the placebo arm primarily because of more diarrhea and worse emotional function in the flutamide-treated group.[33][Level of evidence: 1iC]
    2. A meta-analysis of 27 randomized trials of 8,275 patients comparing conventional surgical or medical castration with MAB—castration plus prolonged use of an antiandrogen such as flutamide, cyproterone acetate, or nilutamide—did not show a statistically significant improvement in survival associated with MAB.[9][Level of evidence: 1iA]

      When trials of androgen suppression versus androgen suppression plus either nilutamide or flutamide were examined in a subset analysis, the absolute survival rate at 5 years was better for the combined-therapy group (2.9% better, 95% CI, 0.3–5.5); however, when trials of androgen suppression versus androgen suppression plus cyproterone acetate were examined, the absolute survival trend at 5 years was worse for the combined-therapy group (2.8% worse, 95% CI, -7.6 to +2.0).[9]

    3. The Agency for Health Care Policy and Research (AHCPR) (now AHRQ) has performed a systematic review of the available randomized, clinical trial evidence of single hormonal therapies and total androgen blockade performed by its Technology Evaluation Center, an evidence-based Practice Center of the Blue Cross and Blue Shield Association. A meta-analysis of randomized trials comparing various hormonal monotherapies in men with stage III or stage IV prostate cancer (predominantly stage IV) came to the following conclusions:[34][Level of evidence: 1iiA]
      • OS at 2 years using any of the LH-RH agonists is similar to treatment with orchiectomy or 3 mg per day of DES (HR, 1.26; 95% CI, 0.92–1.39).
      • Survival rates at 2 years are similar or worse with nonsteroidal antiandrogens compared with orchiectomy (HR, 1.22; 95% CI, 0.99–1.50).
      • Treatment withdrawals, used as a surrogate for adverse effects, occurred less with LH-RH agonists (0%–4%) than with nonsteroidal antiandrogens (4%–10%).

      Total androgen blockade was of no greater benefit than single hormonal therapy and with less patient tolerance. Also, the evidence was judged insufficient to determine whether men newly diagnosed with asymptomatic metastatic disease should have immediate androgen suppression therapy or should have therapy deferred until they have clinical signs or symptoms of progression.[35]

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