The last several years have seen the development of several journals dedicated solely to prostate cancer and prostate-related diseases, and the number of articles published relating to prostate cancer has increased exponentially. Thus, it is understandable that a review of the literature on advanced prostate cancer, such as that provided by Drs. Hussain and Dawson, is by necessity one painted in broad strokes, with any detailed descriptions relegated to the use of examples illustrating larger concepts. Drs. Hussain and Dawson are to be commended for their ambitious undertaking.
The principal thrust of this article is a discussion of therapeutic options for patients with advanced prostate cancer. The paper is divided into sections on first-line hormonal therapy, second-line hormonal therapies, chemotherapy, treatment of bone metastases, and investigational agents. These sections are preceded by an important section entitled "Evaluation of Response to Treatment." However, the discussion in this section applies only to patients with hormone-refractory prostate cancer (HRPC). The consensus criteria referenced by the authors were, in fact, developed only for HRPC patients who are being treated with cytotoxic agents in phase II trials. These criteria cannot be extrapolated for use in patients with hormone-sensitive disease. Even extrapolation to HRPC patients with prostate-specific antigen (PSA)-only disease—an important and rapidly growing group of patients—needs to be addressed cautiously. In addition to the articles cited in this section, investigators at the University of Michigan must receive credit for having also reported that PSA decreases of more than 50% (among patients treated with estramustine [Emcyt] and etoposide on sequential clinical trials) correlated with prolonged survival.
The authors appropriately make the point that a significant advantage of combined androgen blockade over gonadal androgen suppression alone has not been clearly demonstrated, and although not cited, the most recent meta-analysis certainly supports this conclusion. However, it is worth noting that these trials, by and large, have only studied the efficacy of early vs late addition of an antiandrogen, since the gonadal androgen suppression arm frequently allowed the addition of an antiandrogen at progression. Thus, conclusions about the utility of antiandrogens altogether cannot be drawn from these studies.
Secondly, the majority of these studies were undertaken in patients with metastatic disease. As noted by the authors, more and more patients are receiving hormonal therapy prior to the development of metastatic disease, and the relative role of combined androgen blockade in these patients remains to be elucidated.
This review also discusses issues surrounding the optimal timing of androgen deprivation. The authors cite a 1997 Medical Research Council report as evidence supporting the early use of hormones. While this report is provocative, its study design has received considerable criticism. For example, one concern is that many patients randomized to the delayed hormone arm never received hormones at all. Stronger, more compelling evidence supporting earlier initiation of androgen deprivation was presented by Messing et al, who concluded that immediate androgen deprivation in lymph node-positive patients prolongs survival.
Alternatives to Conventional Androgen Ablation
The authors also review the development of therapeutic alternatives to conventional androgen deprivation. The authors’ contention that "gonadal androgen suppression plus or minus antiandrogen therapy remains the most effective first-line treatment" is in contradistinction to two important series,[4,5] which suggested that monotherapy with high-dose bicalutamide (Casodex) may be as efficacious as gonadal androgen deprivation, and is clearly less toxic.
The potential role of intermittent androgen deprivation in delaying the onset of HRPC, as well as the amelioration of some of the side effects associated with its use, are also reviewed by Drs. Hussain and Dawson. In addition to the US Intergroup study mentioned by the authors, a study led by the National Cancer Institute of Canada (which is evaluating intermittent androgen deprivation therapy in patients with a rising PSA after definitive local therapy) should also be cited.
Whether the time a patient can be kept off androgen suppression indeed shortens gradually with sequential cycles of intermittent hormone ablation requires confirmation. A potential explanation for the shorter periods off therapy reported in one series  involves earlier reinitiation of treatment due to physician bias. Overall, it is too early to draw any conclusions about the ultimate utility of intermittent androgen deprivation therapy.
Second-Line Hormone Therapy
The observation that antiandrogen withdrawal results in a 15% to 30% response rate in patients who had previously been considered hormone refractory has opened the door to further exploration of a variety of second-line hormonal manipulations. For example, recent work has defined the efficacy of the estrogenic herbal product PC-SPES in androgen-independent prostate cancer patients. Surprisingly, several series have reported uniform activity of PC-SPES (in about 50% of patients).[7,8] The extent to which this activity is modulated by the estrogenic effects of this compound is under investigation.
The concept that the development of mutations in the androgen receptor result in androgen independence has proven to be an oversimplification of what is clearly a very complex process. Recent data from 185 bone marrow samples collected from HRPC patients by the Cancer and Leukemia Group B suggest that androgen-receptor mutations are rare. While the clinical correlates of this trial have not yet been reported, it is apparent that the interaction between androgen and its receptor reflects a complex system of promoters, inhibitors, and regulating elements.
The use of estramustine and taxane combinations in prostate cancer has clearly become more widespread, and has made huge inroads into the market previously dominated by mitoxantrone (Novantrone). Three principal questions remain to be addressed in the context of these regimens. First, can efficacy be increased by the addition of other agents? For example, triple regimens of estramustine and paclitaxel (Taxol) with either carboplatin (Paraplatin) or etoposide have been explored.
The second question—whether estramustine is required at all—is borne out of the observation that this agent is associated with considerable toxicity, including nausea and thromboembolic events. Investigators in the Hoosier Oncology Group randomized 201 patients to receive vinblastine, with or without estramustine. Overall survival was not significantly different, but favored the combination arm (11.9 vs 9.2 months), with 25% of patients achieving a PSA response, compared with 3% of patients on vinblastine alone. These observations are particularly important in light of the fact that in phase II trials, single-agent docetaxel (Taxotere) produced a PSA response in 46% of patients, compared with 69% of patients when the taxane was used in combination with estramustine.[13,14]
Thirdly, the myelosuppression observed with both docetaxel and paclitaxel has been addressed by use of a weekly dosing schedule for these agents, and this approach is currently being evaluated in a large randomized trial.
By definition, a published discussion of developing therapeutics will always be outdated, but, as in this article, can give the reader a sense of emerging technologies. For example, the mention of trials of the matrix metalloproteinase inhibitor AG3340 in combination with mitoxantrone/prednisone is essentially moot because this agent is no longer being developed. Similarly, while the use of trastuzumab (Herceptin) to target the HER2 receptor is attractive, recent conflicting data on the frequency of HER2/neu overexpression in prostate cancer[15,16] raise questions about the utility of this approach.
A novel approach with positive results reported recently at the 2000 meetings of CaPCure (a national prostate cancer group), was the use of an endothelin antagonist, which had a clear impact on time to progression in a randomized clinical trial.
Finally, immunotherapeutic approaches to the treatment of prostate cancer have been maturing in the last several years. It has been well demonstrated that immune manipulations can break tolerance to common antigens, eliciting both T- and B-cell responses to both known and novel antigens. Although the true clinical impact of these observations has yet to be fully elucidated, the potential for strategies based on these findings is vast.
In short, Drs. Hussain and Dawson are to be complimented for this review of established and emerging therapies in a very broad clinical arena. This article provides a good overview of state-of-the-art treatment for advanced prostate cancer. It is encouraging that the explosion of information in this area may well mandate that future versions of such an update be broken into two or more focused reviews.
1. Smith DC, Dunn RL, Strawderman MS, et al: Change in serum prostate-specific antigen as a marker of response to cytotoxic therapy for hormone refractory prostate cancer. J Clin Oncol 16:1835-1837, 1998.
2. Prostate Cancer Trialists’ Collaborative Group: Maximum androgen blockade in advanced prostate cancer: An overview of the randomized trials. Lancet 355:1419-1497, 2000.
3. Messing EM, Zmanola J, Sarosdy M, et al: Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl J Med 341:1781-1788, 1999.
4. Boccardo F, Rubagotti A, Barichello M, et al: Bicalutamide monotherapy vs flutamide plus goserelin in prostate cancer patients: Results of an Italian Prostate Cancer Project Study. J Clin Oncol 17:2027-2038, 1999.
5. Iversen P, Tyrrell CJ, Kaisary AV, et al: Bicalutamide monotherapy compared with castration in patients with nonmetastatic locally advanced prostate cancer: 6.3 years of follow-up. J Urol 164:1579-1582, 2000.
6. Chaudhary UB, Grossfeld GD, Reese DM, et al: Intermittent androgen deprivation: Patterns of failure in clinically localized prostate cancer (abstract 309). Proc Am Soc Clin Oncol 19:333a, 2000.
7. Small EJ, Frohlich MW, Bok R, et al: Prospective trial of the herbal supplement PC-SPES in patients with progressive prostate cancer. J Clin Oncol 18:3595-3603, 2000.
8. Oh WK, George DJ, Kantoff PW: Activity of the herbal combination PC-SPES in androgen-independent prostate cancer patients (abstract 1334). Proc Am Soc Clin Oncol 19:339a, 2000.
9. Taplin ME, Rajeskumar B, Woda BA, et al: Androgen receptor analyses in androgen independent prostate cancer: Cancer and Leukemia Group B (CALGB) 9663 (abstract 1297). Proc Am Soc Clin Oncol 19:330a, 2000.
10. Kelly WK, Zhu AX, Curley T, et al: Intravenous estramustine, paclitaxel, and carboplatin in patients with advanced prostate cancer (abstract 1364). Proc Am Soc Clin Oncol 19:347a, 2000.
11. Smith DC, Esper P, Strawderman M, et al: Phase II trial of oral estramustine, oral etoposide, and intravenous paclitaxel in hormone refractory prostate cancer. J Clin Oncol 16:1664-1671, 1999.
12. Hudes G, Einhorn LH, Ross E, et al: Vinblastine vs vinblastine plus oral estramustine phosphate for patients with hormone refractory prostate cancer: A Hoosier Oncology Group and Fox Chase Network phase III trial. J Clin Oncol 17:3160-3165, 1999.
13. Picus J, Schultz M: Docetaxel (Taxotere) as monotherapy in the treatment of hormone refractory prostate cancer: Preliminary results. Semin Oncol 26:14-18, 1999.
14. Savarese D, Taplin ME, Halabi S, et al: A phase II study of docetaxel, estramustine, and low-dose hydrocortisone in men with hormone refractory prostate cancer: Preliminary results of Cancer and Leukemia Group B trial 9780. Semin Oncol 26:39-44, 1999.
15. Reese DM, Small EJ, Waldman FM, et al: HER2 expression in androgen-independent prostate cancer (abstract 1365). Proc Am Soc Clin Oncol 19:347a, 2000.
16. Kaltz-Wittmer C, Klenk U, Glaessgen A, et al: FISH analysis of gene aberrations in advanced prostatic cancinomas before and after androgen deprivation therapy. Lab Invest 80:1455-1464, 2000.