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Chemotherapy for Advanced Prostate Cancer: 25 Years Later

The University of Texas M.D. Anderson Cancer Center, Houston, TX

When the article entitled "Doxorubicin, Mitomycin-C, and 5-Fluorouracil (DMF) in the Treatment of Metastatic Hormonal Refractory Adenocarcinoma of the Prostate, With a Note on the Staging of Metastatic Prostate Cancer"¹ was published in the Journal of Clinical Oncology, there was great skepticism that chemotherapy had any role in the treatment of advanced prostate cancer. This was largely based on three justifiable concerns:

1. Elderly prostate cancer patients would neither desire nor tolerate the rigors of chemotherapy.
   
2. Prostate cancer was inherently resistant to chemotherapy based on its low proliferation rate.
   
3. Efficacy of chemotherapy could not be assessed based on the lack of measurable disease or other objective measures of patient benefit.
   

Twenty-five years later, the perception that patients with advanced prostate cancer are either unwilling or too infirm to receive chemotherapy is known to be false. Indeed, the strong impression of some early investigators that chemotherapy could effectively palliate cancer-related symptoms such as pain and asthenia was subsequently definitively demonstrated by Slack and Murphy² and Tannock et al.³ Recently reported data from large randomized studies confirm that a significant proportion of patients with far-advanced disease are able to tolerate chemotherapy, and those that are symptomatic are palliated significantly. Finally, randomized trials have demonstrated a survival benefit from docetaxel-based therapy, and thus chemotherapy is now established as a palliative useful tool that modestly alters the natural history of castrate-resistant metastatic prostate cancer.^4,5 In addition, investigators have made advances in understanding and reducing the severity of the adverse effects of sustained androgen ablation, including use of antiandrogens without testicular suppression, intermittent androgen suppression, and bone-preserving bisphosphonates. These advances allow more patients to tolerate therapy at the time of progression to a castrate-resistant state. Increased awareness of prostate cancer and the emergence of patient advocacy groups demanding care have combined with the advances in the therapeutic armamentarium to overcome the reluctance to use chemotherapy for patients with advanced prostate cancer.

While the general perception that castrate-resistant prostate cancer is inherently chemotherapy-resistant has been largely overcome, it remains true that the prolongation of survival in patients with advanced prostate cancer is modest and effective treatment combinations have yet to be developed. Furthermore, and in contrast with other common solid tumors such as breast and bladder cancer, we have no evidence of improved efficacy with the earlier application of chemotherapy in prostate cancer.^6-10 Optimization of chemotherapy combinations in the setting of advanced cancer followed by the methodical integration in earlier disease settings has been the hallmark of successful therapy development in solid tumors. These milestones have yet to be achieved in prostate cancer. The absence of reported benefit may be a result of the relative paucity of completed large randomized studies. While there are still yet unpublished, ongoing large randomized studies, the published data on early use of chemotherapy is disappointing. Tumor regression observed in the preoperative setting has been a reliable surrogate for chemotherapy efficacy in other solid tumors. The experience to date with preoperative chemotherapy demonstrates little tumor regression¹¹ in early prostate cancer. If the predictive value of tumor regression also holds true for prostate cancer, then a unique therapy development paradigm will need to be developed. Thus, while advanced, castrate-resistant disease has shown some response to chemotherapy, cumulative experience continues to reinforce the notion that early prostate cancer is refractory to the cytotoxic paradigm.

Introduction of the serum prostate-specific antigen (PSA) to monitor disease progression has transformed the care of patents with early prostate cancer. However, serum PSA concentration has not been accepted as a surrogate for patient benefit, and the practice of using PSA concentration to guide clinical decisions in advanced prostate cancer threatens our ability to conduct trials based on more meaningful end points such as objective progression or survival. Although PSA has raised patient awareness, improved detection, and provided a tool for monitoring progression of early-stage prostate cancer, it has not translated into improved efficiency of clinical studies in patients with advanced prostate cancer. Thus, we still have challenges to define objective criteria for outcomes that reliably correlate with survival.

Our sense that the distribution of visceral metastases and volume of bone involvement are related to therapy response and patient survival is now amply confirmed and accounted for by morphologic variants that reflect the biologic heterogeneity of prostate cancer.^12-16 Furthermore, it is reasonable to implicate the bone microenvironment in progression of those prostate cancers with clinical presentations dominated by bone-forming metastases. Several lines of clinical and experimental observations have generated interest in developing strategies to prevent or treat bone metastases.^16-17 Despite this, the further characterization of patient populations based on the distribution of metastases and the incorporation of markers of bone remodeling into studies has not gained the expected interest. Although the benefit of this approach is not established, recent clinical studies suggest that markers of bone remodeling may be important for prognostication and, at the least, will more fully characterize patients into relevant categories of risk.

Future therapy advances in prostate cancer may hinge on developing a new therapy paradigm. For those patients with bone metastases, an integrated strategy of chemotherapy and bone-targeting therapy may be required. To effectively test such a strategy requires development of markers to predict and monitor bone metastases. The approach may differ from that applied to patients with visceral metastases, where the more conventional solid tumor therapy paradigm may apply and where the underlying biology is very different. Optimal integration of systemic therapy with control of the primary may be required for selected high-risk patients.^18,19

The treatment paradigm used as a framework to develop effective therapy for prostate cancer may be analogous to that successfully used for leukemia. Critical to the successes achieved in leukemia have been the link between the underlying biology, clinical presentation, and response to therapy. Access to relevant tissue facilitated the development of a clinically relevant classification that overcame the challenge of heterogeneity and allows for the effective monitoring of therapeutic consequences.

Fortunately, our understanding of prostate cancer biology has improved over the last decade, providing a framework in which to develop treatment strategies and to identify markers. Ideally, candidate markers will reflect clinically relevant milestones of prostate cancer progression: progression within the primary site, risk for metastases, and progression within the bone environment. Access to such markers will facilitate development of rational treatment strategies that will likely incorporate chemotherapy. The goal of our efforts should be to develop a balanced approach of parallel screening of new therapeutic agents and combinations of agents with the development of markers that will be used to characterize and monitor the prostate cancer.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

AUTHOR CONTRIBUTIONS

Manuscript writing: Christopher J. Logothetis, Randall Millikan

Final approval of manuscript: Christopher J. Logothetis, Randall Millikan

REFERENCES

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13. McDonnell TJ, Troncoso P, Brisbay SM, et al: Expression of the proto-oncogene bcl-2 in the prostate and its association with the emergence of androgen-independent prostate cancer. Cancer Res 52:6940-6944, 1992[Abstract/Free Full Text]

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16. Tu SM, Millikan RE, Mengistu B, et al: Bone-targeted therapy for advanced androgen-independent carcinoma of the prostate: A randomized phase II trial. The Lancet 357:336-341, 2001

17. Mathew P, Thall PF, Bucana CD, et al: Platelet-derived growth factor receptor inhibition and chemotherapy for castration-resistant prostate cancer with bone metastases. Clin Cancer Res 13:5816-5824, 2007[Abstract/Free Full Text]

18. Assikis VJ, Do KA, Wen S, et al: Clinical and biomarker correlates of androgen-independent, locally aggressive prostate cancer with limited metastatic potential. Clin Cancer Res 10:6770-6778, 2004[Abstract/Free Full Text]

19. Bolla M, Gonzalez D, Warde P, et al: Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med 337:295-300, 1997[Abstract/Free Full Text]

This Article Full Text (PDF) From JCO 1983 Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Alert me to new issues of the journal Save to my personal folders Download to citation manager Google Scholar Articles by Logothetis, C. J. Articles by Millikan, R. PubMed Articles by Logothetis, C. J. Articles by Millikan, R.