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Management of Progressive Metastatic Prostate Cancer

Management of Progressive Metastatic Prostate Cancer

This review succinctly summarizes a relatively large body of literature surrounding the treatment of advanced, stage D2 (M+) prostate cancer. However, the patient with classic stage D2 prostate cancer, presenting de novo with multiple sites of bony metastasis, pain, and other systemic symptoms, is becoming less common in clinical practice. In 1997, prostate cancer is most commonly diagnosed in a locally advanced form, either clinically or pathologically stage C (T3), and accounts for approximately 60% of all newly diagnosed cases in the United States.[1] The reasons for this “stage migration” undoubtedly lie in the widespread use of prostate-specific antigen (PSA) for the detection of prostate cancer while still organ-confined, and in the use of PSA to monitor patients who have undergone definitive local treatment.

Androgen Deprivation Therapy

In concert with this stage migration, androgen deprivation therapy is being applied to the treatment of patients with T3 and even earlier stages of the disease, although the value of this approach is not altogether certain. Justification for early initiation of androgen deprivation therapy comes from several sources. In a widely cited Radiation Therapy Oncology Group (RTOG) trial,[2] patients with stage T3 prostate cancer (and a small number with metastases to pelvic lymph nodes) were randomized to receive radiation therapy with or without 4 months of neoadjuvant hormonal therapy (a luteinizing hormone–releasing hormone [LHRH] analog plus a nonsteroidal antiandrogen). While survival was not statistically different between the two groups of patients after a median observation period of 3.3 years, local progression of prostate cancer was more common in patients who received radiation alone, as was biochemical recurrence of the disease, as defined by PSA. Neoadjuvant hormonal therapy has also been employed prior to prostatectomy, with a reduction in the incidence of positive surgical margins,[3] but the impact of this approach on the natural history of the disease is uncertain.

Unfortunately, many patients with organ-confined and locally advanced prostate cancer will experience a recurrence of their disease despite local treatment, with or without the use of neoadjuvant hormonal therapy. Because of the use of PSA in monitoring such patients, recurrence will be detected not only before patients become symptomatic but also before the disease can be detected with conventional radiographic techniques. This group of patients again poses a dilemma. Should they opt for observation and no treatment until symptomatic disease occurs, or should androgen deprivation therapy be introduced as soon as the PSA is clearly on the rise? While a definitive answer is not available, there is literature to suggest that early intervention with androgen-deprivation therapy is advantageous [see reference 4].

Immediate vs Delayed Therapy

In a Veterans Administration Cooperative Urologic Research Group (VACURG) study of various doses of diethylstilbestrol (DES) vs placebo in men with minimally symptomatic advanced prostate cancer, a survival advantage was observed for patients receiving 1 mg/d of DES.[4] In fact, the men who were assigned to placebo therapy did eventually receive hormonal therapy, eg, DES or orchiectomy, at the time of symptomatic disease progression, and, thus, this trial is best viewed as a trial of immediate vs delayed hormonal therapy. In the recent intergroup trial of leuprolide(Lupron) vs leuprolide plus flutamide (Eulexin) in patients with newly diagnosed D2 prostate cancer,[5] the more significant, 19 month survival advantage associated with combination therapy in patients with minimal amounts of metastatic disease suggests that early, aggressive treatment may be advantageous.

However, many men who are found to have a rising PSA as the only evidence of disease recurrence cannot tolerate the side effects (eg, hot flashes and impotence) of combined androgen blockade (an LHRH analog plus a nonsteroidal antiandrogen), and, hence, alternative strategies for producing androgen deprivation are being investigated. Examples include the use of intermittent therapy with an LHRH analog plus a nonsteroidal antiandrogen or, alternatively, the combination of a 5-alpha-reductase inhibitor and a non- steroidal antiandrogen.

Thus, although there has been little change in the therapeutic armamentarium for the treatment of advanced prostate cancer, there is the perception that we may be altering the natural history of the disease as the result of earlier detection and earlier intervention with androgen-deprivation therapy.

Palliation... or More?

In the abstract of the Waselenko/Dawson article, the statement is made that “the major focus of treatment has shifted to palliation and quality of life.” While physicians caring for patients with advanced prostate cancer should keep palliation of disease-related symptoms and maintenance of quality of life as important goals, I do not think that our patients or our society wish us to be content with these goals alone. The palliative benefits arising from therapy with mitoxantrone (Novantrone) and prednisone are certainly significant in and of themselves, but they are also significant because they suggest that chemotherapy does, in fact, possess antitumor activity in this disease.

While still bleak, an entirely nihilistic view of chemotherapy in the treatment of advanced prostate cancer is no longer appropriate. Moreover, the combination of mitoxantrone plus prednisone is now a well-defined regimen against which potentially more active cytotoxic therapies may be compared. If the estramustine (Emyct) plus taxane regimens continue to demonstrate the high degree of activity that they have exhibited during phase I evaluation, a randomized comparison to mitoxantrone plus prednisone would be the next logical step. The estramustine plus taxane regimen not only may provide better palliation of disease-related symptoms but also may possess sufficient antitumor activity to create a survival advantage.

Although medical oncologists continue to explore the role of cytotoxic agents in the management of advanced prostate cancer, they are anxious for the availability of more novel treatments, whether those treatments target aberrant signal transduction events in the prostate cancer cell[6] or take the form of genetic manipulation.[7]


1. Crawford DE: Changing paradigms in the treatment of advanced prostate cancer. Adv Oncology 12:14-21, 1996.

2. Pilepich MV, Krall JM, al-Sarraf M, et al: Androgen deprivation with radiation therapy compared with radiation therapy alone for locally advanced prostatic carcinoma: A randomized comparative trial of the Radiation Therapy Oncology Group. Urology 45:616-623, 1995.

3. Soloway MS, Sharifi R, Wajsman Z, et al: Randomized prospective study comparing radical prostatectomy alone vs radical prostatectomy preceded by androgen blockade in clinical stage B2 (T2bNxM0) prostate cancer. J Urol 154:424-428, 1995.

4. Byar DP, Corle DK: Hormone therapy for prostate cancer: Results of the Veterans Administration Cooperative Urological Research Group Studies. J Natl Cancer Inst Monogr 7:165, 1988.

5. Crawford ED, Eisenberger MA, McLeod DG, et al: A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med 321:419-424, 1989.

6. Gao X, Grignon DJ, Chbihi T, et al: Elevated 12-lipoxygenase mRNA expression correlates with advanced stage and poor differentiation of human prostate cancer. Urology 46:227-237, 1995.

7. Song-Chu K, Akinobu G, Thalmann GN, et al: Molecular therapy with recombinant p53 adenovirus in an androgen-independent, metastatic human prostate cancer model. Hum Gene Ther 7:1683-1691, 1996.

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